{"paper_id":"6ae85d38-5487-4cab-8b42-fe31b5075093","body_text":"J Cell Signal. 2026\nVolume 7, Issue 1\nJournal of Cellular Signaling Review\n1\nJ Cell Signal.  2026;7(1) :1–20.\nShared Biology Underlying Benign Endometrial Diseases and \nEndometrial Cancer: Current Knowledge and Future Prospectives\nY ara Aljubran1, Warren B. Nothnick1,2,3,4,*\n1Departments of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, USA 66160\n2Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA 66160\n3Obstetrics and Gynecology, University of Kansas Medical Center, Kansas City, KS, USA 66160\n4Center for Reproductive Sciences, University of Kansas Medical Center, Kansas City, KS, USA 66160\n*Correspondence should be addressed to Warren B. Nothnick, wnothnic@kumc.edu\nReceived date: November 24, 2025, Accepted date: January 12, 2026\nCitation: Aljubran Y , Nothnick WB. Shared Biology Underlying Benign Endometrial Diseases and Endometrial Cancer: Current \nKnowledge and Future Prospectives. J Cell Signal. 2026;7(1):1–20.\nCopyright: © 2026 Aljubran Y , et al. This is an open-access article distributed under the terms of the Creative Commons Attribution \nLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are \ncredited.\nIntroduction\nThe uterus is an essential female organ required for \nthe propagation of all mammalian species. The uterus is \ncomposed of two major tissue layers, the endometrium, which \nis the inner layer as is further classified as the functionalis or \nbasalis layer whose major functions are to provide the site of \nattachment of implanting embryos and to give rise to a new \nfunctionalis layer with regeneration of the endometrial lining \nwhich occurs with each menstrual cycle. The myometrium is \nthe muscular tissue component of the uterus which is critical \nfor contractions during labor and delivery. The endometrial \nlining is composed of three major cell types, the endometrial \nluminal epithelial cells, the glandular epithelial cells and \nthe stromal cells. Endometrial cancer [1,2] develops when \nendometrial glands become hyperplastic and invasive \ndeveloping first within the endometrium ( Stage IA; Figure \n1) and then spreading to the underlying myometrium ( Stage \n1B; Figure 1 ) with both limited to the uterine body. Stage \nII tumors typically invade into cervical stromal connective \ntissue, but without invading beyond the uterus, while stage \nIII tumors may invade local or regional structures beyond the \nuterus including the lymph nodes. Adenomyosis is defined \nas growth of endometrial epithelial glands and surrounding \nstroma which develop within the myometrium ( Figure 1 ) \nwhile endometriosis is composed of both glands and stroma \nwhich develop ectopically in the pelvic cavity (Figure 1). In the \ncase of endometriosis, these lesions can develop throughout \nthe pelvic cavity with the majority of lesions developing \non the ovary, the peritoneal lining and in the cul-de-sac. \nEndometrial cancer cells, adenomyotic epithelial and stromal \ncells and endometriotic epithelial and stromal cells all exhibit  \nAbstract\nThe endometrium is thought to serve as the precursor tissue for diseases of the uterus such as endometrial cancer, adenomyosis, and \nendometriosis.  More specifically, endometrial glands are proposed to be the source of developing endometrial cancer within the uterine \nbody while ectopic endometrial glands and surrounding stroma which develop within the myometrium give rise to adenomyosis, and those \nthat establish outside of the uterus give rise to endometriosis.   While adenomyosis and endometriosis are benign diseases, they do share \nseveral cellular characteristics with endometrial cancer including enhanced cell survival/proliferation, migration and invasion. Further, the \npathophysiology of these diseases is driven by unopposed estrogen and each exhibit various degrees of progesterone resistance and altered \ndownstream expression and/or function of genes relevant to epithelial-to-mesenchymal transition, tissue remodeling and transcriptional \nsignaling. In this review we summarize our current understanding on differences and similarities in major cell signaling pathways among \nendometrial cancer, adenomyosis and endometriosis. In closing, we emphasize the necessity for additional studies to delve deeper into \ncommon attributes in the pathophysiology of these diseases towards the goal of identifying novel, non-hormonal therapies for their treatment.\nKeywords: Endometrial cancer, Adenomyosis, Endometriosis, Protease, Protease inhibitor, Tissue remodeling, Epithelial-to-mesenchymal \ntransition, Steroid receptor, Transcription factor\n\nAljubran Y, Nothnick WB. Shared Biology Underlying Benign Endometrial Diseases and Endometrial Cancer: Current \nKnowledge and Future Prospectives. J Cell Signal. 2026;7(1):1 –20.\nJ Cell Signal. 2026\nVolume 7, Issue 1\n2\ncharacteristics of enhanced estrogen signaling and reduced \nprogesterone action including augmented cell proliferation, \nmigration and invasion. Key players in the pathophysiology \ninclude the sex steroid receptors, mediators of epithelial-to-\nmesenchymal transition (which contribute to cell migration \nand invasion), proteases and protease inhibitors and \ntranscription factors. In the following paragraphs, we examine \nthe expression  of steroid receptors, epithelial-mesenchymal \ntransition proteins, proteases, protease inhibitors, and \ntranscription factors among these three endometrial diseases. \nTo do so, we evaluated the literature through a search of \nthe PUBMED/MEDLINE database. Search terms included \npublications with  “endometrial cancer” , “adenomyosis” and \n“endometriosis” in the title. Each disease was separately \nassessed in conjunction (and) with “steroid receptor” , or \n“epithelial-mesenchymal-transition” , or “protease”/”protease \ninhibitor” or “transcription factor” in the article title. \nSteroid Receptors Expression in Malignant and \nBenign Endometrial Diseases\nEndometrial cancer\nBoth the level of expression and cellular localization of \nthe steroid receptors, estrogen receptor and progesterone \nreceptor are critical for normal responses of the endometrium \nto the sex hormones estrogen and progesterone, respectively \n[3].  Estrogen receptor (ER) is known for its role in increasing \ncell proliferation during the proliferative phase of the female \nmenstrual cycle, while progesterone receptor (PR) is known to \nblock estrogen-induced proliferation of endometrial glands \nand promote stromal cell proliferation and differentiation.  \nHowever, these steroid receptors have differing patterns of \nexpression in endometrial cancer and diseases of the uterus \n[4–6]. A systematic review and meta-analysis by Zhang and \ncolleagues [5] strongly support the notion that in subjects \nwith endometrial cancer there is an inverse relationship \nbetween the levels of ER and PR and survival. More recently, a \ncollaborative study by a European Network for Individualized \nTreatment of Endometrial Cancer [6], identified distinct \nclinical outcomes based upon level of ER and PR expression \nlevel. Cutoff values of 0–10% ER/PR positive was associated \nwith unfavorable outcomes, 20–80% was associated with \nintermediate outcomes (defined as) while 90–100% was \nassociated with favorable outcomes. Di Nezza and colleagues \nfurther explore how reduced PR expression may impact \nthe pathophysiology of EC. In this study they discovered \nthat progesterone inhibits the expression of matrix \nmetalloproteinases (MMPs), thus suppressing mechanisms \nsuch as extracellular matrix degradation and the processing \nof growth factors and cytokines that aid and promote \ncancer cells to invade [7]. Fujimoto and colleagues observed \na decrease in the mRNA levels of ER-α and ER-β, and an \nupregulation in ERR α in relation to clinical stage, myometrial \ninvasion, and dedifferentiation ( Table 1 ) [8]. On the other \nhand, some studies postulate that in cancer patients who \nare obese, there is an upregulation of steroid receptors. \nThis signifies a possible link between the two. For example, \npatients with positive PR expression were most often young \nand obese [9], and additionally, those who were obese had a \nhigher probability of having an ER or PR-positive tumor [10]. \nFrom these studies it is clear that low ER and PR expression \nis associated with advanced endometrial cancer and poor \noutcomes.\nFigure 1. Graphic depiction of endometrial cancer, adenomyosis, and endometriosis localization within the female reproductive tract.\n\n\nAljubran Y, Nothnick WB. Shared Biology Underlying Benign Endometrial Diseases and Endometrial Cancer: Current \nKnowledge and Future Prospectives. J Cell Signal. 2026;7(1):1 –20.\nJ Cell Signal. 2026\nVolume 7, Issue 1\n3\nAdenomyosis\nCompared to EC, there is limited information on ER and \nPR expression in adenomyosis as well as inconsistencies \nbetween findings regarding steroid receptor expression in \nadenomyosis. For example, Tamaya and colleagues evaluated \nsteroid receptor levels in ten cases of adenomyosis utilizing \nScatchard plot analysis [11]. It was found that the expression of \nboth ER and androgen receptor (AR) was detected in each case, \nwhile PR was not detected in the majority of cases. Similarly, \nusing tissue microarray and dendrogram cluster analysis, Jian-\nJun Wei and colleagues found that the larger the tumor size, \nthe more downregulated ER and PR expression was [12]. A \nmorphometric investigation and evaluation of cytokeratin, \nvimentin, and steroid receptor content was conducted by \nDonnez and colleagues to compare what they initially thought \nto be endometriotic nodules of the rectovaginal septum \nwith peritoneal endometriosis [13]. By the end of the study, \na new type of adenomyoma was categorized, specifically \nrectovaginal adenomyoma, and their results demonstrated \nthat the expression of ER and PR content in this type of lesion \nwas significantly lower compared to eutopic endometrium \ntissue [13]. \nIn contrast to other studies, Maria Sztachelska and colleagues, \nin a study in which the function and expression of ER and PR \nwere evaluated confirmed the presence of ER and PR at both \ngene and protein levels and an upregulation of membrane \nprogesterone receptors α and β [14]. Another study found that \nERβ expression was significantly high in adenomyotic lesions \nbut declined with increasing lesional fibrosis, while there was \nno significant difference in ERα expression in comparison to \ncontrol tissues. They determined that with increased fibrosis \nin ectopic endometrium, estrogen signaling decreases [15]. \nMehasseb and colleagues detected reduced levels of ER-α in \neutopic and ectopic (adenomyosis) endometrium in subjects \nwith adenomyosis compared to those without, while ER-β \nexpression was increased in adenomyotic functionalis glands \nduring the proliferative phase. Similar to ER-α expression, \nPR-A and PR-B expression in the basalis stroma, and inner and \nouter myometrium were reduced compared to controls [16] \n(Table 2).\nEndometriosis\nA Scatchard plot analysis was utilized by Tamaya and \ncolleagues to determine the expression levels of steroid \nreceptors in endometriosis [11]. In comparison to normal \nendometrium tissue, the ER and PR levels were lower in \nendometriosis tissues. An immunohistochemical analysis \ncarried out by Nisolle and colleagues assessed the differences \nin proliferative activity throughout the menstrual cycle \nTable 1. Steroid receptors in endometrial cancer.\nSteroid Receptor Expression References\nER- β Downregulated in EC [8]\nER- α Downregulated in EC [8] \nERR- α Upregulated in EC [8] \nER Inverse relationship between ER and survival\nHigher in obese patients\n[5]\n[9,10]\nPR Inverse relationship between PR and survival\nInhibits MMPs, suppresses growth factors and extracellular matrix degradation\nHigher in obese patients\n[5]\n[7]\n[9,10] \nTable 2. Steroid receptors in adenomyosis.\nSteroid Receptor Expression References\nER While its expression has been detected, it is decreased in adenomyoma comparison to \neutopic tissue.\n[11–13,15]\nER- α Reduced levels in eutopic and ectopic endometrium [16] \nERβ Decreased expression as lesional fibrosis increases\nElevated expression during proliferative phase\n[15]\n[16] \nPR While its expression has been detected, it is decreased in adenomyoma comparison to \neutopic tissue.\nDownregulation detected\n[12,13]\n \n[16]\nmPR α Upregulated in adenomyosis [14] \n\nAljubran Y, Nothnick WB. Shared Biology Underlying Benign Endometrial Diseases and Endometrial Cancer: Current \nKnowledge and Future Prospectives. J Cell Signal. 2026;7(1):1 –20.\nJ Cell Signal. 2026\nVolume 7, Issue 1\n4\nbetween eutopic and ectopic endometrium [17]. It was \nobserved that while the eutopic endometrium was not \nproliferatively active during the late secretory phase, the \nectopic endometrium was, and instead of decreasing, PR \nexpression in the glandular epithelium and ER expression \nin the glandular epithelium and stroma stayed consistent \n(Table 3). A study by Pluchino and colleagues using tissue \nmicroarray and immunohistochemistry demonstrated that in \nendometriosis, ER-α, PR, AR, and aromatase were expressed \n[18]. Specifically, as the severity of the symptoms experienced \nby patients was evaluated, it was determined that ER- α was \nlinked to the differences in severity, with higher levels being \nmore severe. Fazleabas and colleagues discovered through \nRT-PCR and immunocytochemistry that while PR and ER-α \nwere expressed in both eutopic and ectopic endometrium, \nER-β was only found in ectopic endometriotic lesions, thus \nsignifying its upregulation in the disease [19]. Aromatase was \nadditionally detected, but specifically ten months after the \nbaboons were inoculated with menstrual endometrium to \ninduce experimental endometriosis. In a study that examined \nboth the expression of ER-α and ER- β, low expression levels of \nER-α, and higher levels of expression of ER- β were observed \n[20]. The expression of steroid receptor coactivators has been \nfound to differ between eutopic and ectopic tissue samples \nas well. \nEpithelial-to-Mesenchymal Transition (EMT) \nProteins in Malignant and Benign Endometrial \nDiseases\nEndometrial cancer\nEpithelial-mesenchymal transition (EMT) induces the \nspread of many diseases and cancers, including endometrial \ncancer (EC). EMT occurs when the epithelial cells transform \ninto mesenchymal cells as they gain migratory and invasive \ncharacteristics [21]. The cells lose their cell polarity and cell-\nto-cell adhesion. E-cadherin (CDH1), a protein that regulates \ncellular signaling and tumor suppression, is a biomarker \nof EMT. In general, it is downregulated in EMT. Zhou and \ncolleagues observed that a high expression of E-cadherin in \nEC, which was caused by an upregulation of SOX17, is linked \nto a better prognosis ( Table 4 ) [22]. As mentioned earlier, \nZEB1, or Zinc finger E-box binding homeobox 1 (ZEB1) is \na transcription factor linked to EMT. Xiao and colleagues \nsilenced ZEB1 and observed that this decreased cell migration \nand invasion [23]. They also found that the β -catenin/TCF4 \nsignaling feedback stimulated ZEB1 transcription. ZEB2, along \nwith SLUG, are overexpressed in EC, and act as predictors of \nhigher FIGO stages [24]. In one study, it was found that bone \nmorphogenetic protein 2 (BMP2) induced EMT by activating \nTable 4. EMT proteins in endometrial cancer.\nTable 3. Role of steroid receptors in endometriosis.\nSteroid Receptor Expression References\nER Lower expression in endometriotic tissue.\nInstead of decreasing during the late secretory phase, levels remained constant\n[11]\n[17]\nPR Lower expression in endometriotic tissue\nInstead of decreasing during the late secretory phase, levels remained constant\n[11]\n[17]\nER-α The higher its expression, the more severe the disease\nLower expression\n[18]\n[20]\nER-β Upregulated in endometriosis [19,20]\nEMT Proteins Expression References\nE-cadherin Higher expression is linked to a better prognosis\nWhen migration was inhibited, its expression increased\n[22]\nZEB1 Induces EMT [23]\nZEB2 Higher expression linked to higher FIGO stages [24] \nSnail Linked to a worse prognosis [26]\nSLUG Higher expression linked to higher FIGO stages [24]\nBMP2 Triggers EMT by SLUG or SNAIL [25]\nPiwil1 Causes an increase in mesenchymal markers and suppresses E-cadherin [27]\n\nAljubran Y, Nothnick WB. Shared Biology Underlying Benign Endometrial Diseases and Endometrial Cancer: Current \nKnowledge and Future Prospectives. J Cell Signal. 2026;7(1):1 –20.\nJ Cell Signal. 2026\nVolume 7, Issue 1\n5\nfactors such as SLUG or SNAIL [25]. Snail has been linked to a \nworse prognosis for EC [26].  Piwil1 is an oncogene-like stem \ncell protein that is upregulated in EC. Chen and colleagues \nwere able to determine that Piwil1 has a role in increasing \nmesenchymal markers and suppressing E-cadherin, which \nresults in an EMT-like phenotype [27].\nAdenomyosis\nIn a study by Zheng and colleagues in which the role of focal \nadhesion kinase (FAK) was evaluated, they determined that \nit is upregulated in adenomyosis and may regulate the EMT \nthrough the FAK/phosphoinositide 3-kinase (PI3K)/protein \nkinase B (AKT) pathway ( Table 5 ) [28]. Many studies have \ndiscovered a link between E-cadherin and EMT in adenomyosis. \nWhen decreased, migration and invasion are induced [29]. \nN-cadherin, on the other hand, is found to be upregulated \nin adenomyosis, specifically when EMT is induced, which \nis why it is considered a characterization of a mesenchymal \nphenotype [29,30]. More specifically, Yoo and colleagues \nproposed that β -catenin activates TGF- β induced EMT, as \nthere was a strong correlation between β -catenin and TGF- \nβ2 in women with this disease [31]. Overall, β-catenin activity \npromotes EMT in adenomyosis. High activity levels of Notch1, \na transmembrane receptor in which its signaling pathway \nregulates cellular signaling, were observed by Bourdon and \nassociates in adenomyosis-induced mice. As Notch1 activation \ncorrelated with elevated levels of immune and EMT markers, \nincluding E-cadherin, Vimentin, Tgfβ, Snail1, and Slug, Snail3, \nit was concluded that Notch1 activation corresponds with \nthe atypical expression of these markers in the progression \nof adenomyosis [32]. SPARC-related modular calcium binding \n2 (SMOC2) is an extracellular matrix-associated protein. Its \noverexpression results in the upregulation of N-cadherin \nand alpha-SMA – another mesenchymal marker – as well as \nthe downregulation of E-cadherin. This suggests that SMOC2 \npromotes EMT [33]. Hu and colleagues aimed to determine \nthe role of transmembrane glycoprotein neuropilin 1 (NRP1) \nin EMT by infecting endometrial cells with NRP1 retroviruses \nso as to upregulate NRP1. A mesenchymal phenotype, \ndownregulation of E-cadherin, upregulation of alpha-SMA \nand N-cadherin, and enhanced migration were observed. In \ncontrast, NRP1 shRNA inhibited EMT. This signifies its possible \nrole in the EMT and the progression of adenomyosis [34]. Similar \nto endometrial cancer, several EMT proteins are misexpressed \nin adenomyosis. ZEB1 is elevated in endometrial adenomyosis \ntissue, and its upregulation is modulated by SKP1 and SKP2 \n[35] in eutopic adenomyosis endometrial stromal cells. Qi and \ncolleagues [29] reported that Notch1, N-cadherin, Snail and \nSlug were upregulated in eutopic endometrial tissue from \nadenomyosis patients compared to normal endometrium \nwhile E-cadherin expression was reduced.\nEndometriosis\nLike endometrial cancer and adenomyosis, E-cadherin \nexpression is reduced in endometriosis ( Table 6). Gaetje and \nassociates first reported that endometriotic epithelial cells \nlack E-cadherin expression which was associated with cell \ninvasion in vitro and that E-cadherin negative epithelial cells \nwere increased in endometriotic tissue compared to controls \n[36]. Sirtuin 1(SIRT1) is a protein that deacetylates transcription \nfactors to impact gene expression. When overexpressed in \nendometriotic epithelial cells, it inhibits oncogene induced \nsenescence and is therefore able to trigger EMT [37]. Enhancer \nof Zeste homolog 2 (EZH2) has been identified as an enzyme \nthat promotes EMT in endometriosis. Its overexpression \nupregulated Snail, Slug, and vimentin expression, while it \ndownregulated E-cadherin. When inhibited, the opposite \noccurred, resulting in the restoration of the epithelial \nTable 5. EMT proteins in adenomyosis.\nEMT Proteins Expression References\nFocal Adhesion Kinase (FAK) Upregulated in adenomyosis; regulates EMT through FAK/PI3K/AKT pathway [28] \nE-cadherin Inhibits EMT and migration/invasion [29]\nN-cadherin Induces EMT and migration/invasion. Upregulated in eutopic endometrial tissue of \nadenomyosis patients\n[29,30]\nβ -catenin Induces EMT [31]\nTGF β-2 Induces EMT [31] \nSMOC2 Promotes EMT by upregulating mesenchymal markers and downregulating E-cadherin [33]\nNotch1 Upregulated [29,32]\nNRP1 Overexpression caused a mesenchymal phenotype, downregulated E-cadherin, and \nupregulated mesenchymal markers\n[34] \nZEB1 Elevated in adenomyosis tissue; modulated by SKP1 and SKP2 [35]\nSlug Upregulated in eutopic endometrial tissue of adenomyosis patients [29] \nSnail Upregulated in eutopic endometrial tissue of adenomyosis patients [29]\n\nAljubran Y, Nothnick WB. Shared Biology Underlying Benign Endometrial Diseases and Endometrial Cancer: Current \nKnowledge and Future Prospectives. J Cell Signal. 2026;7(1):1 –20.\nJ Cell Signal. 2026\nVolume 7, Issue 1\n6\nphenotype of the EECs and a reduction in migration and \ninvasion [38]. Huang and colleagues evaluated the role of \nmatrix metalloproteinase-9 (MMP-9) through a statistical \nanalysis and discovered that there is a higher concentration \nof MMP-9 in EMT patients, and these concentrations are \nproportional to the stage of the disease [39]. Regarding \nthe mesenchymal markers, TWIST1, SNAIL, and SLUG were \noverexpressed, while CDH1, or E-cadherin, expression was \ndownregulated. MYC is another protein associated with \nendometriosis. It was concluded that both TWIST1 and MYC \ninduce EMT, resulting in the development of endometriotic \nlesions [40]. Snail was additionally found to be activated by \nβ-catenin/TCF-3 in endometriosis. β -catenin knockdown \nresulted in the inhibition of oestrogen-induced Snail mediated \nEMT [41]. Wu and colleagues determined that ZEB1 has a vital \nrole in inducing endometriosis, as it was overexpressed, along \nwith EMT markers Vimentin and N-cadherin. When ZEB1 was \ndownregulated, migration, invasion, and EMT of the Ishikawa \ncells were inhibited [42].\nIn summary, among the three diseases, E-cadherin expression \nappears to be reduced, while ZEB1, Snail and Slug expression \nare elevated in each case and associated with cell migration/\ninvasion. \nProtease/Protease Inhibitor Expression in Malignant \nand Benign Endometrial Diseases\nEndometrial cancer\nProteases play a crucial role in regulating endometrial \ndiseases, which can be used to the advantage during \ntreatment. For example, Huang and colleagues determined \nthat ubiquitin-specific protease 31 (USP31) can be used to \nforetell a prognosis. Those with lower levels of USP31 will most \nlikely have a worse prognosis, and vice versa [43] ( Table 7). \nAnother protease serves a similar function. The expression of \nHtrA serine peptidase 1 (HtrA1) is inversely related to tumor \ngrade. Its downregulation increased the invasiveness of  \npapillary serous EC cell lines, and its upregulation decreased \ntheir invasive ability [44]. Another important group of \nproteases is cathepsins, which are generally found within \nlysosomes. In comparison to normal endometrium, an \nupregulation of Cathepsin B has been observed in EC tissues. \nWhen suppressed, it resulted in a decrease in proliferation [45]. \nIt has also been found to be correlated with the FIGO stage of \nEC [46]. Cathepsin D additionally could aid in the prognosis \nthrough immunohistochemical detections [47]. Lower levels \nof expression are correlated with a worse prognosis [48]. \nSkrzypczak and associates collected data supporting the \npossibility that cysteine protease cathepsin L (CTSL2) may \nhave a role in the progression of EC. It was highly expressed, \nand it had a positive correlation with the expression of \ngrowth regulatory genes [49]. One study discovered that \nthe caseinolytic mitochondrial matrix peptidase proteolytic \nsubunit (CLPP) plays a vital role in the proliferation of type \nI EC cancer tissue. Its upregulation in EC suggested that it \nmay also play a role in removing damaged mitochondrial \nproteins [50]. Another protease that may affect EC and its \nprognosis is hepsin, a type II transmembrane serine protease. \nThere is an inconsistency of findings regarding its role in \nendometrial cancer. Matsuo and colleagues concluded that \nit is overexpressed in EC, and the higher its level of protein \nexpression, the more advanced the cancer is [51]. However, \nNakamura and colleagues determined that Hepsin, the gene \nthat encodes for the protein hepsin, instead inhibits cell \ngrowth [52]. \nMatrix metalloproteinases (MMPs) are key proteases \nwhich degrade the extracellular matrix and contribute to \ncell migration and invasion [53]. Among the numerous \nMMPs, MMP-2 and MMP-9 have been the most studied \nin endometrial cancer. Aglund and colleagues [54] first \nreported that overexpression of both MMP-2 and MMP-9 were \nassociated with poor patient survival. More recent studies \nhave demonstrated in vitro functionality of MMP2 and MMP9 \nusing cell assays. SPOCK2, which was reported to be lower \nin endometrial cancer, was demonstrated in vitro to mediate \nTable 6. EMT proteins in endometriosis.\nEMT Proteins Expression References\nE-cadherin Reduced expression [36] \nSIRT1 Triggers EMT by inhibiting apoptosis [37] \nEZH2 Overexpression induces EMT by upregulating mesenchymal markers [38] \nMMP9 Higher concentration in EMT patients than healthy controls [39] \nTWIST1 Induces EMT [40] \nSLUG Overexpressed [40] \nSNAIL Overexpressed [40] \nβ -catenin Activates Snail; knockdown inhibits estrogen-induced Snail mediated EMT [41] \nZEB1 Overexpression induced migration and EMT [42] \n\nAljubran Y, Nothnick WB. Shared Biology Underlying Benign Endometrial Diseases and Endometrial Cancer: Current \nKnowledge and Future Prospectives. J Cell Signal. 2026;7(1):1 –20.\nJ Cell Signal. 2026\nVolume 7, Issue 1\n7\ncell proliferation, invasion and migration by mediating MMP2 \n(and MT1-MMP) expression and action [55], while Wang and \ncolleagues [56] demonstrated that MMP2 could be inhibited \nby over-expression of the mature form of IL-37 (IL137b∆1-45) \ndecreased cell migration and invasion by inhibiting MMP2 \nexpression. Targeting of MMP-9 to reduce cell proliferation, \nmigration and/or invasion was demonstrated in three \nindependent studies. Ruan and associates [57] demonstrated \nthat miR-183 up-regulation in endometrial cancer cells targets \nMMP-9 expression to augment cell proliferation and invasion \nin vitro , while Zhao and colleagues [58] reported that the \nlong non-coding RNA, GATA6-AS, is reduced in endometrial \ncancer tissue and cell lines and that its overexpression in \nvitro augments cell proliferation, reduced cell apoptosis by \nmediating MMP-9 expression.\nThe net result of protease action is a combination of \nexpression of the protease as well as that of the respective \nprotease inhibitors [59]. Thus, several of the inhibitors of \nthe aforementioned proteases have been examined in the \ncontext of EC. The expression of protease inhibitors has been \nfound to significantly impact the progression of endometrial \ncancer. Plasminogen activator inhibitor type 1 (PAI-1) inhibits \nproteases important in fibrinolysis. A study found high levels \nof PAI-1, as well as PAI-1 4G/5G polymorphism, in the blood \nof endometrial cancer patients, indicating a vital role in EC. \nThe higher the PAI-1 level, the higher the grade [60]. Another \nprotease inhibitor that is upregulated in EC is SERPINA3. \nYang and colleagues discovered that it modulates the G2/M \ncheckpoint of the cell cycle and additionally inhibits cell \ndeath [61]. Human epididymis protein 4 (HE4) is a protease \ninhibitor that can signify a worse prognosis for EC patients \n[62]. Its expression increases with the clinical stage. When \noverexpressed, proliferation is promoted and malignant \nphenotypes are enhanced [63]. The upregulation of protein \nZ-dependent protease inhibitor (ZPI), as well as its cofactor \nprotein Z (PZ), in EC cells also indicate that they play a role in \nendometrial cancer [64]. They were not expressed in normal \ntissues. On the other hand, hepatocyte growth factor activator \ninhibitors HAI-1 and HAI-2 are downregulated in EC. Their \ndecrease is associated with a worse prognosis. Nakamura \nand colleagues observed that they have an inhibitory effect \non EC cell migration and invasion, which is achieved through \ndecreasing matriptase and hepsin levels. These protease \ninhibitors reduced ER and PR signal transduction, reduced \nthe expression of mesenchymal markers, and increased that \nTable 7. Proteases and protease inhibitors in endometrial cancer.\nProteases Expression References\nUSP31 Downregulated in EC; inverse relationship with prognosis [43] \nHtrA1 Downregulated in EC; inverse relationship with tumor grade [44] \nCathepsin B Upregulated in EC [45,46] \nCathepsin D Downregulated in EC; can be used to assess prognosis [47,8] \nCTSL2 Upregulated in EC; may cause the progression of EC [49] \nCLPP Increased expression; may play a role in removing damaged mitochondrial proteins [50] \nHepsin Inhibits cell growth\nUpregulated in EC\n[51]\n[52]\nMMP-2 Upregulated in EC\nInhibition reduces cell proliferation, migration, invasion\n[54]\n[55,56] \nMMP-9 Upregulated in EC\nInhibition reduces cell proliferation, migration, enhances apoptosis\n[54]\n[57,58] \nProtease Inhibitors Expression References\nPAI-1 High expression; associated with grade of cancer [60] \nSERPINA3 Upregulated: regulates G2/M checkpoint and inhibits apoptosis [61] \nHE4 Overexpression associated with worse prognosis [62,63] \nZPI Upregulated [64] \nHAI-1 & HAI-2 Downregulated; their expression inhibits proliferation [65] \nBortezomib Increased mRNA expression of caspases-3 and caspases-9; decreased mRNA expression of bcl-2 [66] \nTIMP-2 Elevated in blood serum [67] \nTIMP-1 Decreased expression\nIncreased expression\n[67]\n[68]\n\nAljubran Y, Nothnick WB. Shared Biology Underlying Benign Endometrial Diseases and Endometrial Cancer: Current \nKnowledge and Future Prospectives. J Cell Signal. 2026;7(1):1 –20.\nJ Cell Signal. 2026\nVolume 7, Issue 1\n8\nof epithelial markers [65]. Lastly, bortezomib, a treatment for \nsome cancers, may also be able to affect endometrial cancer \ncells. In an Ishikawa cell line, bortezomib decreased the \nmRNA expression of bcl-2, a protein that inhibits apoptosis, \nwhile it increased the mRNA expression of caspases-3 and \ncaspases-9, both of which are activated during apoptosis. \nThus, bortezomib was able to increase the susceptibility of \nIshikawa cells to chemotherapy [66]. Contrary to bortezomib, \nthe appearance of carcinoma and benign neoplasms are \ncorrelated with TIMP-2 elevation in the blood serum. On the \nother hand, there were lower TIMP-1 levels in endometrial \ncancer patients in comparison to controls and patients with \npolyps and hyperplasia. The researchers concluded that \nthey cannot be considered diagnostic markers but can be \nused in the prognosis process [67]. Additionally, TIMP-1 was \nupregulated in a high risk patient group [68].\nAdenomyosis\nIn a study that evaluated how adenomyosis impacted the \ncoagulation and fibrinolysis system during menstruation, 50% \nof the patients had an increase in thrombin-antithrombin \ncomplex (TAT) and plasmin-alpha 2-plasmin inhibitor complex \n(PIC). According to Yamanaka and colleagues, this data \nindicates that adenomyosis patients are at risk of developing \nthrombosis, infarction, and exacerbated menorrhagia [69]. \nMenorrhagia could be caused by activated fibrinolysis during \nmenstruation. Mori and colleagues investigated the effects \nof orally active-matrix metalloproteinase (MMP) inhibitor \n(ONO-4817) on mice with uterine adenomyosis. There was a \nlower probability that adenomyosis would progress in mice \ntreated with ONO-4817. Mice with 1% ONO-4817 had less \nprogression in the uteri, specifically 2.71 ± 0.93, with the \ndegree of pathological progression graded from 1 to 5, while \nthe uteri that was not exposed had 4.33 ± 0.75. Additionally, \nONO-4817 inhibited the invasion of stromal cells into the gel, \nindicating that ONO-4817 could be potent in suppressing \nthe development of adenomyosis [70]. Many studies have \ndiscovered that matrix metalloproteinases are upregulated in \nadenomyosis lesions. MMP-2 and MMP-9 specifically are most \noften elevated (Table 8) [71]. As a result, some have concluded \nthat they may play a role in the invasion of endometrial tissues \ninto the myometrium [72]. In the endometrial stromal cells \nof patients with adenomyosis, there was a higher secretion \nof TIMP-1 in comparison to those without the disease [73]. \nOn the other hand, in active adenomyosis, there was a lesser \nexpression of TIMP-1, TIMP-3, and TIMP-4, a decrease in the \noccurrence of apoptosis, and more proliferation by glandular \nand stromal cells [74].\nEndometriosis\nThere are a variety of proteases that regulate endometriosis. \nFor one, Porter and associates supported their hypotheses \nthat cysteine cathepsins promote tissue invasion and \nlesion establishment, and when inhibited it could block the \nattachment of endometriosis lesions with the data collected \nfrom their study. Cathepsins L and K were significantly \nupregulated in the endometriotic lesions of both mice and \nhumans in comparison to other tissues, and when inhibited \nby E-64, there were much less attached endometriosis \nlesions [75]. Cathepsin G concentration was additionally \nsignificantly higher in endometriosis tissues ( Table 9 ) [76]. \nCalcium-activated neutral protease 7 (CAPN7) is a protease \nthat upregulates MMP-2, thus promoting human endometrial \nstromal cell (hESC) migration and invasion [77]. Thrombin \nalso activated MMP-2 in endometriotic stromal cells (ESCs). \nThis was suppressed by thrombin inhibitor d-phenylalanyl-\nl-prolyl-l arginine chloromethyl ketone (PPACK). The \nresearchers concluded that the thrombin system stimulates \nthe inflammatory response of endometriotic cells and \nmitogenic activity [78]. Kusama and associates discovered \nthat thrombin induces transformations similar to epithelial-\nmesenchymal transition (EMT) and fibroblast to myofibroblast \ntransdifferentiation [79]. \nTissue remodeling is an important process regulated by \nMMPs and TIMPs. There are conflicting observations regarding \nthe concentration of MMP-2 in endometriotic tissues. Tang \nand associates discovered that the promoter regions of MMP2, \nas well as MMP3 and MMP7, underwent notable changes in \nendometriotic lesions in comparison to eutopic tissue during  \nTable 8. Proteases and protease inhibitors in adenomyosis.\nProteases Expression References\nMMP-2 Elevated expression [71] \nMMP-9 Elevated expression [71]\nProtease Inhibitors Expression References\nTAT Increases risk of developing thrombosis, infarction, and exacerbated menorrhagia [69] \nONO-4817 Suppressed development of adenomyosis [70] \nTIMP-1 Higher secretion in those with adenomyosis than those without.\nDecrease in expression\n[73] \n[74]\nTIMP-3 & TIMP-4 Decrease in expression [74] \n\nAljubran Y, Nothnick WB. Shared Biology Underlying Benign Endometrial Diseases and Endometrial Cancer: Current \nKnowledge and Future Prospectives. J Cell Signal. 2026;7(1):1 –20.\nJ Cell Signal. 2026\nVolume 7, Issue 1\n9\nthe proliferative phase [80]. Chen and colleagues found that \nMMP2 expression decreased with disease [81], while Malvezzi \nand colleagues observed that in infertile women, its levels \nincreased in stage III/IV in comparison to women with stage I/II \nendometriosis [82]. MMP-9 is overexpressed in endometriotic \ntissues [83]. Additionally, there is elevated expression of \nmembrane-type 5 metalloproteinase (MT5-MMP) in eutopic \nendometrium and a greater amount of transcript levels in \nmost peritoneal lesions [84]. An immunohistochemistry \ndemonstrated strong staining in luminal epithelial cells. \nPut together with the results of an rt-PCR, it was deduced \nthat MT5-MMP expression leads to an increase in tissue \nremodeling and cell migration. In red peritoneal and ovarian \nendometriosis, MMP1 mRNA expression was detected, \nbut not in black peritoneal and rectovaginal lesions [85]. \nIts expression was also linked to tissue remodeling and \nbleeding, with a possible role in the secondary shedding and \nreimplantation of endometriotic lesions.\nThe development of endometriosis may be regulated \nby Ubiquitin Specific Protease 7 (USP7). It is upregulated \nin ectopic endometrial stromal cells (EECs), promoting \nirregular behavior and regulating the expression of DNA \nmethyltransferase 1 (DNMT1), a protein that when silenced, \nsuppresses the oncogenic characteristics caused by USP7 \n[86]. Furthermore, the overexpression of ubiquitin-specific \nprotease 10 (USP10) is also linked to migration, proliferation, \nand suppression of apoptosis. Chen and colleagues believe it \naccomplishes this by activating the Raf-1/ERK kinase (MEK)/\nextracellular signal-regulated kinase (ERK) signaling pathway \n[87]. Finally, one protease that is instead downregulated in \nendometriosis is high temperature requirement A1 (HtrA1).  \nProtease Expression References\nCathepsins L & K Upregulated; when inhibited, less endometriotic lesions can attach [75] \nCathepsin G High concentrations [76] \nCAPN7 Upregulates MMP-2 and promotes migration and invasion of hESC [77] \nMMP-2 Decreased\nOverexpressed, promotes migration and invasion, related to decrease in TIMP-2\n[80]\n[81,82]\nMMP-9 upregulated [83] \nMT5-MMP High transcript levels in peritoneal endometriosis; leads to increase in tissue \nremodeling\n[84] \nMMP-1 Expression detected in red peritoneal and ovarian endometriosis; linked to tissue \nremodeling and bleeding\n[85] \nUSP7 Upregulated, regulates DNMT1, promotes migration and invasion [86] \nUSP10 Activates Raf-1/MEK/ERK signaling pathway and promotes proliferation and \nsuppresses apoptosis\n[87] \nHtrA1 Downregulated [78] \nThrombin Activates MMP-2; promotes changes resembling EMT and FMT [78] \nProtease Inhibitors Expression References\nProtease inhibitor During the luteal phase, downregulated in uterine cavity, upregulated in PT [89] \nSLPI Upregulated in peritoneal fluid [90,91]\nAlpha1-AT Decreased in mice that underwent ovariectomy; could induce inflammation [92] \nKallistatin Downregulation correlated with decrease in severity; increases ROS levels, \nmodulates caspase 3 signaling and MnSOD\n[93] \nA2M Suppressed blastocyte and mouse embryo development [94] \nTIMP-1 Downregulated in endometriosis. In early endometriosis, no significant difference \nin expression\n[95,96] \nTIMP-2 Downregulated in advanced endometriosis [99] \nTIMP-3 Promoter regions changed significantly during proliferative phase [80] \nTIMP-4 Promoter regions changed significantly during proliferative phase [80] \nTable 9. Proteases and protease inhibitors in endometriosis.\n\nAljubran Y, Nothnick WB. Shared Biology Underlying Benign Endometrial Diseases and Endometrial Cancer: Current \nKnowledge and Future Prospectives. J Cell Signal. 2026;7(1):1 –20.\nJ Cell Signal. 2026\nVolume 7, Issue 1\n10\nThe researchers determined that it had a direct correlation \nwith TGFβ1 [88]. \nA multitude of studies have also discovered many protease \ninhibitors that may influence or cause the onset and \nprogression of endometriosis. A comparative study conducted \nby Fazleabas evaluated the general concentration of protease \ninhibitors in women with endometriosis. It was observed that \nduring the luteal phase, there was a decrease in protease \ninhibitor concentration in the uterine cavity, but an increase \nin the peritoneal fluid [89]. Next, both the secretory leukocyte \nprotease inhibitor (SLPI), which inhibits human leukocyte \nelastase, and its gene were significantly upregulated in the \nperitoneal fluid of women [90,91]. In the endometriosis-\nlike grafts of mice that underwent a unilateral ovariectomy \n(uOVX), the expression level of alpha1-antitrypsin (alpha1-\nAT) decreased, which Tamura and colleagues suggested may \ninduce inflammation. It also blocked interleukin-8 expression \n(IL-8; [92]). Mao and associates assessed the role kallistatin \n(KS) plays in endometriosis. It had low levels of expression, \nwhich decreased with the severity of the disease. It was found \nthat it has the ability to increase intracellular reactive oxygen \nspecies (ROS) levels, and it additionally, modulates caspase 3 \nsignaling and manganese superoxide dismutase (MnSOD), \nwhich together inhibit the progression of the disease [93]. \nRecently, the production of alpha-2 macroglobulin (A2M), \na broad-spectrum plasma protease inhibitor, in human \nendometrium was reported. Sayegh and colleagues studied \nits expression and effects on mouse embryo development. \nStrong signaling expression was detected in the secretory \nendothelium compared to proliferative endothelium. The \nblastocyte development of mouse embryos in vitro  was \nsuppressed at A2M concentrations of 400-400 mmol/L. It also \ninhibited mouse embryo development [94]. TIMP-1, the tissue \ninhibitor of metalloproteinases-1, was found in a multitude of \nstudies to have reduced expression in endometriosis [95,96]. \nMadjid and colleagues discovered that in the endometrial \ncells of subjects with decreased TIMP-1 expression had a \nhigher risk of endometriosis [97]. However, one study did not \ndetermine a statistical significance between the difference \nin expression of TIMP-1 in the eutopic endometrium of \nsubjects with early endometriosis and subjects with a \nhealthy endometrium [98]. In late endometriosis, TIMP-2 is \ndownregulated, which could signify an increase in MMP-2 \nas endometriosis advances [99]. Additionally, the promoter \nregions of TIMP3 and TIMP4 underwent notable changes in \nendometriotic lesions in comparison to eutopic tissue during \nthe proliferative phase [80].\nIn summary, each of the three diseases exhibit signs of \ntissue remodeling and invasion. Not surprisingly, increases \nin protease expression has been reported in each of these \ndiseases while the expression of protease inhibitor expression \nis less consistent, some report reduction while others have \nbeen reported to be elevated.\nTranscription Factor Expression in Malignant and \nBenign Endometrial Diseases\nEndometrial cancer \nA variety of transcription factors have been found to \nsignificantly impact endometrial cancer through their \nregulation of gene expression. Firstly, Yang and colleagues \nevaluated the effect the knockdown of E2F1 has on EC, and \nit was discovered that it inhibited invasion and metastasis, \nthus allowing one to conclude that it regularly promotes \na malignant phenotype ( Table 10 ) [100]. Another study \nsupports this conclusion, as it identified a strong correlation of \nE2F1 with EC [101]. This study additionally found that HMGA1 \nand PGR are closely correlated with EC. A different form of \nE2F1, E2F7, was highly expressed in EC, and its silencing may \nsuppress the effect RAD51AP1 overexpression has on cell \ngrowth [102]. It is important to note that many endometrial-\nmesenchymal transition (EMT) proteins mentioned in an \nearlier section, such as Notch1 [103], SNAIL [104] and SLUG \n[105], are also transcription factors, and their expression, \nwhether its elevated or lowered, plays a significant role in \nthe development of endometrial cancer, adenomyosis, and \nendometriosis. \nHMGA2 is a transcription factor known to promote cancer. \nOne study observed its upregulation in endometrial cancer, \nwhich was linked to a worse prognosis, as its overexpression \npromoted proliferation, migration, invasion, and drug \nresistance. HMGA2 knockdown had the opposite effects \n[106]. Another transcription factor in which its upregulation \nwas observed in EC is T-Box transcription factor (TBX2). Ding \nand colleagues discovered it enhanced cell resistance to \nchemotherapy by regulating the nuclear factor erythroid \n2-related factor (NRF2) pathway [107]. It was additionally \nfound to suppress ferroptosis by upregulating ferroptosis \nsuppressor protein 1 (FSP1; [108]. Transcription factor 19 \n(TCF19), known to be differentially expressed in microsatellite \nstable and instable, was linked to a worse prognosis and \nimmune exhaustion signature in endometrial cancer \npatients. It promoted tripartite motif-containing 14 (TRIM14) \ntranscription, which induced tumorigenicity [109]. Repressor \nElement 1 (RE1) silencing transcription factor (REST), on \nthe other hand, was downregulated in human EC samples. \nWhile it was highly expressed in the cell lines, the decrease in \nexpression is linked to an increase in proliferation [110].\nThere are many significant transcription factors in \nendometrial cancer that are a part of the forkhead box family. \nTo start, FOXP1, a P subfamily, was differently expressed in \nhuman samples based on the phase of the menstrual cycle \nand the grade of malignancy. There was a reduction in its \nimmunostaining during the early secretory stage in the basalis \n[111]. Additionally, its expression was reduced in the nucleus  \n\nAljubran Y, Nothnick WB. Shared Biology Underlying Benign Endometrial Diseases and Endometrial Cancer: Current \nKnowledge and Future Prospectives. J Cell Signal. 2026;7(1):1 –20.\nJ Cell Signal. 2026\nVolume 7, Issue 1\n11\nand cytoplasm of grade 3 EC in comparison to grades 1 and \n2. This study concluded that FOXP1 is specifically involved in \nestrogen dependent ECs as well. Next, the overexpression of \nforkhead transcription factor 1 (FOXO1) was observed to inhibit \ncell proliferation, migration, invasion, and tumorigenesis. \nIn these cells, sterol regulatory element-binding protein 1 \n(SREBP1), another transcription factor, was downregulated, \nwhich may signify that FOXO1 targets SREBP1 [112]. SREBP1 \nis usually upregulated in EC and promotes tumorigenesis. \nAnother transcription factor of the forkhead box family is \nforkhead box A1(FOXA1). When downregulated, Abe and \ncolleagues observed that proliferation was promoted. Thus, \nFOXA1 could potentially be a tumor suppressor [113]. FOXO3 \nwas found to be associated with SIRT1 [114]. SIRT1 induces \nFOXO3 deacetylation and activity. Overexpression of SIRT1 \nleads to proliferation, migration, invasion, and an inhibition \nof apoptosis. Two transcription factors of the homeobox \ngene family were found to play a role in EC. When HOXA10 \nwas downregulated, endometrial hyperplasia began to \ndevelop in animals [115]. On the other hand, elevated levels \nof HOXB9 indicated a worse prognosis, as it was upregulated \nin EC and associated with histological grade and lymph node \nmetastasis [116]. Two transcription factors of the Kruppel-\nlike transcription family were detected. The expression of \nKruppel-like factor 2 (KLF2) resulted in the in inhibition of \nEC proliferation through the suppression of nuclephosmin 1 \n(NPM1) transcription [117]. On the other hand, Krüppel-like \nfactor 12 (KLF12) was found to be overexpressed in EC, which \nwas associated with an increase in proliferation and tumor \nsize, a decrease in apoptosis [118]. Additionally, Dong and \ncolleagues demonstrated that when Krüppel-like factor 17 \n(KLF17), a transcription factor, induced EMT and cell invasion, \nthe expression of TWIST1 increased [119]. This is because KLF17 \ntransactivates TWIST1 expression by binding to its promoter. \nInterestingly, ETV4 has been found to control ER activity, a key \noncogene of endometrial cancer, as well as the development \nof EC [120]. ETV5 is overexpressed in Hec1A EC cells and has \nbeen found to induce the EMT [121]. The study additionally \nTable 10. Transcription factors in endometrial cancer.\nTranscription Factor Expression References\nE2F1 Knockdown inhibited invasion and migration\nClosely correlated with EC\n[100] \n[101] \nE2F7 Highly expressed. Silencing could suppress proliferative effects of RAD51AP1 [102] \nHMGA2 Upregulation associated with worse prognosis. It promoted proliferation, migration, invasion, and \ndrug resistance\n[106]\nTBX2 Upregulated in EC; enhances cell resistance by regulation of NRF2; upregulates FSP1 to suppress \nferroptosis\n[107,108]\nTCF19 Linked to worse prognosis [109] \nREST Downregulation linked to proliferation [110] \nFOXP1 Lowered expression in early secretory phase, and in nucleus and cytoplasm of grade 3 EC [111] \nFOXO1 Inhibits proliferation and migration; may target SREBP1 (it induces tumorigenesis) which was \ndownregulated\n[112] \nFOXA1 Could be tumor suppressor because its downregulation promoted proliferation [113] \nHOXA10 Downregulation induced development of EC hyperplasia in animals [115] \nHOXB9 Upregulated in EC; linked to worse prognosis [116] \nKLF2 Expression inhibits EC proliferation by suppressing NPM1 [117] \nKLF12 Overexpressed in EC; increases proliferation and decreases apoptosis [118] \nKLF17 Induces EMT and cell invasion. Transactivates TWIST1 expression [119] \nETV4 Controls EC development and ER signaling [120] \nETV5 Overexpression leads to EMT; regulates NID1 and NUPR1 [121] \nSIRT1 Overexpression of SIRT1 leads to proliferation, migration, invasion, and an inhibition of apoptosis; \nenhances deacetylation of FOXO3\n[114] \nATF3 Downregulated; expression can inhibit proliferation, JunB expression, and promote apoptosis [122] \nATF4 Overexpressed [123]\nNFAT5 Expression increases with grade [124] \nNF1C Inhibited proliferation, motility, and invasion of HECs [64]\n\nAljubran Y, Nothnick WB. Shared Biology Underlying Benign Endometrial Diseases and Endometrial Cancer: Current \nKnowledge and Future Prospectives. J Cell Signal. 2026;7(1):1 –20.\nJ Cell Signal. 2026\nVolume 7, Issue 1\n12\ndiscovered that ETV5 regulates the protein expression of \nNidogen 1 (NID1) and Nuclear Protein 1 (NUPR1). Together, an \ninvasive phenotype is achieved. Similarly, from the activating \ntranscription factor family, ATF3 and ATF4 were detected. \nATF3 was observed to be downregulated in endometrial \ncancer cells. When overexpressed, it inhibits proliferation, \nJunB expression, a transcription factor upregulated in EC \nand promotes apoptosis [122]. Liu and associates discovered \nthat ATF4 is normally upregulated in EC cell lines, and its \nknockdown inhibits tumor growth [123]. Two transcription \nfactors of the nuclear factor family were found to have different \neffects on endometrial cancer. Nuclear factor of activated T \ncells 5 (NFAT5) expression increased with grade [124], while \nNuclear Factor 1-C (NF1C) inhibited the proliferation, motility, \nand invasion of human uterine endometrial cancer cells [63].\nAdenomyosis\nCompared to endometrial cancer, there is a paucity of work on \ntranscription factors and adenomyosis. Expression of two zinc-\nfinger transcription factors, GATA binding proteins, 2 and 6, were \ndetermined by immunohistochemistry. GATA2 had a two-fold \nlower expression while GATA6 a four-fold higher expression \nin ESCs of adenomyosis patients ( Table 11 ) [125]. These \nlevels impaired ESC decidualization. Another transcription \nfactor that impairs decidualization is transcription factor 21 \n(TCF21). It achieves this by inhibiting decidual markers and \ncytoskeleton alterations [126]. STAT3 is a transcription factor \nknown to play a significant role in endometrial regeneration. \nAccording to Hiraoka and colleagues, its activation promotes \nadenomyosis. In Stat3-deficient mice, a decrease in lesions \nand expression of genes associated with tissue regeneration \nwere observed in c comparison to control mice (STAT3; [127]. \nIn one study enacted by Li and colleagues, notably higher \nexpressions of NF-κB DNA-binding activity, which was linked \nto dysmenorrhea severity, and p50 and p65 were detected \n[128]. It was concluded that NF-κB could be a transcription \nfactor of great significance regarding the development of \nadenomyosis. Nie and colleagues additionally collected data \nsignaling an elevation in expression of p50, p65, and p52, and a \ndownregulation in progesterone receptor isoform B (PR-B) and \na decrease in its immunoreactivity [129]. Lupicka and associates \nhypothesized that disturbances in stem cell differentiation of \nuterine tissue could be a main promoter of the development \nof adenomyosis. This is backed up by their data. There was a \ndecrease in protein level of NANOG and SOX2 in stromal cells, \nwhile an elevation of OCT4 and SOX2 in the myometrial cells \nof dysfunctional uteri [130]. Two studies observed a decrease \nin mRNA and protein expression of HOXA10 [131]. Only the \nstudy conducted by Guo and colleagues observed a decrease \nin mRNA and protein expression of HOXA11 as well [132].\nEndometriosis\nIn deep infiltrating endometriosis (DIE), Ganieva and \nassociates detected a significant amount of TCF21 expression \nin comparison to normal tissues. Its expression increased with \nseverity of the disease ( Table 12), and it was also determined \nto play a role in the regulation of fibrosis in endometriosis \n[133]. Additionally, Wu and colleagues determined that \nTCF12 plays a role in the pathogenesis of endometriosis, as \nit has a higher expression in endometriotic than endometrial \nstromal cells, a change in its expression significantly impacted \nthe proliferation and invasion of ESCs, and also affected the \nTable 11. Transcription factors in adenomyosis.\nTranscription Factor Expression References\nGATA2 Low expression (H-SCORE) [125] \nGATA6 High expression (H-SCORE) [125] \nTCF21 Impairs decidualization [126]\nSTAT3 Activation promotes adenomyosis; deficiency leads to decrease in lesions [127]\nNF-kB High DNA-binding activity, which was linked to dysmenorrhea severity [128]\np50 High protein expression and immunoreactivity [128,129] \np52 High immunoreactivity [129]\np65 High protein expression and immunoreactivity [128,129]\nPR-B Downregulated and decrease in immunoreactivity [129]\nNANOG Protein level decreased in stromal cells [130]\nSOX2 Protein level decreased in stromal cells, but increase in myometrial cells [130]\nOCT4 Increased protein level in myometrial cells [130]\nHOXA10 Decrease in expression [130,131]\nHOXA11 Decrease in expression [132]\n\nAljubran Y, Nothnick WB. Shared Biology Underlying Benign Endometrial Diseases and Endometrial Cancer: Current \nKnowledge and Future Prospectives. J Cell Signal. 2026;7(1):1 –20.\nJ Cell Signal. 2026\nVolume 7, Issue 1\n13\nbinding activities of other transcription factors like USF2, \nMMP9, and SF-1 [134]. Ntzeros and associates observed a \ndifference in ZEB1 expression in the endometriotic cysts of \nendometrioma cases with and without DIE, which could reflect \ndifferences in their pathogenetic mechanisms [135]. Another \nstudy determined that ZEB1 could be linked to an invasive \ntype of endometriosis. Its expression was only detected in the \nepithelial of endometriotic lesions, not of normal endometria, \nand it was most often found in the epithelial cells of invasive \nendometriosis [136]. AP-1 is another transcription factor \nthat may aid in the development of invasive endometriosis, \nas its expression has been shown in multiple models, and \nit promotes invasive phenotypes [137]. There was a high \nactivation of transcription factor nuclear factor-kappa B (NK-\nkappaB) in red, or active, endometriotic lesions [138]. p50 is \nalso a part of the NF-kappaB family. In p50 knockdown mice, \nthe size of the endometrial implants greatly decreased while \nNF-kappaB activation was interfered with. Additionally, NF-\nYA, NF-YB, and NF-YC are additional nuclear factors with \npossible significant roles in this disease. NF-YA expression \nwas found to be upregulated during the proliferative phase \nin eutopic endometrium. In ectopic endometrium, NF-YB \nand NF-YC were also upregulated [139]. Amirteimouri and \ncolleagues suggested that because of NF-Y’s regulation of ID \ngenes, it may be behind the epigenetic changes that occur \nin endometrial tissues. In severe endometriosis, in which \npatients experienced intense pain, Badary and colleagues \nfound significant expression through immunohistochemistry \nof HIF-1a [140]. Early growth response 1 (EGR) is another \ntranscription factor detected in endometriosis tissues. It was \ndetermined to induce proliferation, migration, and invasion \n[141]. Transcription factors of the GATA family have been \nfound to regulate key genes that impact endometriosis. GATA2 \nregulates genes important for the differentiation of stromal \ncells [142]. It is repressed in endometriotic cells. GATA6 on \nthe other hand, is upregulated in endometriotic cells, inhibits \nGATA2 and promotes endometriotic markers. Likewise, GATA-\n3 promotes proliferation. In a study by Chen and colleagues, \nTable 12. Transcription factors in endometriosis.\nTranscription Factor Expression References\nTCF21 Highly expression in DIE; increases with severity of disease [133,134]\nZEB1 Indicator of invasive endometriosis [135,136]\nEGR1 Induces proliferation, migration, and invasion [141]\nGATA2 Repressed in endometriosis; vital to regulation of genes that control differentiation of \nstromal cells\n[142] \nGATA-3 Promotes proliferation [142]\nGATA6 Upregulated in endometriosis; inhibits GATA2 [142] \nNK-kappaB High activation in red (active) lesions [138]\nNF-YA, B, & C Upregulated [139]\nHIF-1alpha Significant expression in severe endometriosis [140] \nKLF11 Under expressed in human lesions, knockout can cause proliferative lesions in mice [145]\nTFEB Highly expressed – knockdown suppressions lesion growth [146]\nOCT4 Maintains undifferentiated state in tissues; upregulated in endometriosis; expression \ncorrelated with genes that control migration\n[147]\n[148]\nBACH2 Regulates Treg genes; upregulated [149]\nATF4 Expression allows cells to resist ferroptosis [150] \nAP-1 Promotes invasive phenotype [137]\np50 Part of NF-kappaB family – p50 knockdown decreased size of implants; there was \ndisruption in NF-kappaB activation\n[138]\nSOX18 Upregulated – induces EMT, increase invasion and migration, deteriorates endometriosis [144] \nCOUP-TF Detected in both eutopic and endometriotic cells; might inhibit aromatase P450 in eutopic \nendometrial cells\n[151]\nSF-1 Transcription undetected in eutopic endometrial cells; can compete for same DNA-binding \nsite to prevent inhibition caused by COUP-TF in endometriotic stromal cells\n[151] \nHOXA10 Reduced expression in both eutopic and ectopic tissue; reduced eutopic endometrial \nexpression associated with infertility\n[152]\n\nAljubran Y, Nothnick WB. Shared Biology Underlying Benign Endometrial Diseases and Endometrial Cancer: Current \nKnowledge and Future Prospectives. J Cell Signal. 2026;7(1):1 –20.\nJ Cell Signal. 2026\nVolume 7, Issue 1\n14\ncells where GATA-3 was introduced had higher proliferation \nrates than those without GATA-3 [143]. The cells in which it \nwas suppressed had lower proliferation rates than others. In \nIshikawa cells, SOX18 overexpression was found to induce \nEMT, increase proliferation, as well as progress endometriosis \novertime through the growth and bleeding of tissue outside \nof the uterus [144]. KLF11, a gene known to be associated \nwith disease in humans, was found to be under expressed in \nendometriotic tissues of humans. When Klf11 was knocked out \nin mice, their lesions were larger and resembled the lesions of \nhumans with late-stage diseases. In comparison, Klf9 knockout \nhad no significant result on the lesions of the animals [145]. \nAccording to Chen and colleagues, transcription factor EB \n(TFEB) is highly expressed in the endometrium. It improves \nthe proliferative abilities of human endometrial stromal \ncells (HESCs). In rat models, TFEB knockdown suppresses the \ngrowth of lesions [146]. OCT4 is a transcription factor known \nto be an essential to upholding a tissue’s undifferentiated state \n[147]. Chang and colleagues discovered that in endometriotic \ntissues, the expression of OCT4 mRNA, which was upregulated \nin ectopic endometriotic tissues, was associated with genes \nthat regulate migration in the cell [148]. In women who \nultimately develop endometriosis, an increase in inflammation \nin eutopic and ectopic endometrium is observed, which can \nnow be linked to a disruption in the homeostasis of regulatory \nT cells (Treg). BACH2, a transcription factor that regulates Treg \ngenes, is upregulated in these tissues, indicating an iron-heme \noverload response [149]. Additionally, the overexpression of \nATF4 has been found to allow cells to resist ferroptosis that is \ncaused by an iron overload [150]. In a comparison between \nchicken ovalbumin upstream promoter transcription factor \n(COUP-TF) and steroidogenic factor-1 (SF-1), where antibodies \nwere employed against both, it was found that in eutopic \nendometrial cells, only COUP-TF bound to the nuclear \nreceptor half-site (NRHS), while both COUP-TF and SF-1 \ntranscripts were detected in endometriotic tissues [151]. The \nresearchers concluded that as SF-1 expression is undetected \nin eutopic endometrial stromal cells, one of the transcription \nfactors that causes the inhibition of aromatase P450 is COUP-\nTF. However, in endometriotic stromal cells, SF-1 can compete \nfor the same DNA-binding site, thus stopping the inhibition \ncaused by COUP-TF. Lastly, among the transcription factors \ninvestigated in endometriosis pathophysiology, perhaps the \nmost-well studied is HOXA10. Lazim and colleagues recently \npublished a systematic review on the topic [152]. Briefly, the \nmajority of data on this topic would support the notion that \nsufficient data are provided to support the notion that women \nwith endometriosis express low levels of HOXA10 compared \nto women without endometriosis. More specifically, low levels \nof eutopic endometrial HOXA10 expression was associated \nwith infertility which may be due to altered endometrial \nreceptivity, decidualization and/or embryo implantation \nfailure. With respect to ectopic, endometriotic lesion tissue, \nHOXA10 expression is also reduced compared to eutopic \nendometrial tissue.\nIn summary, there is a vast amount of literature on \ntranscription factor expression in each of the three diseases \nbut little consistency among the diseases. Among those \ntranscription factors, HOXA10 has been reported to be reduced \nin all three conditions, with most reports on endometriosis. \nThe bulk of the literature reports GATA2 and GATA6 expression \nin endometriosis and to a lesser extent adenomyosis.\nSummary\nEndometrial cancer, adenomyosis and endometriosis are \ndiseases which arise from the endometrial lining of the \nuterus. Each disease is characterized by augmented cell \nproliferation/survival, migration and invasion. Augmented \nestrogen action and reduced progesterone signaling is \npostulated to contribute these common cellular attributes \namong these diseases. Expression of estrogen and \nprogesterone receptors appear to display similar patterns \namong the three conditions but there is less consistency \nin assessment of epithelial-to-mesenchymal transition \nproteins (such as ZEB2, EZH2) among the three diseases. \nWith respect to EMT protein assessment, there is a larger \nbody of work and consistency in patterns of expression for \nkey proteins such as CDH1, SLUG, SNAIL and ZEB1 between \nendometrial cancer and endometriosis. As all three of these \ndiseases exhibit differing degrees of invasiveness, which is \nlinked to tissue remodeling, there is some consistency with \nrespect to patterns of expression for proteases such as MMP-\n2 and MMP-9 which is elevated in all three diseases. With \nrespect to protease inhibitors, TIMP-1 expression is reduced \nin all three diseases, while TIMP-2 expression is reduced in \nendometrial cancer and endometriosis. While many studies \nhave evaluated expression of different transcription factors \nin endometrial cancer, adenomyosis, and endometriosis, few \nstudies have assessed the same transcription factors.  Thus, \nthere are several factors associated with endometrial cancer, \nadenomyosis and endometriosis, most notably altered \nsteroid receptor expression and imbalances in the MMP/TIMP \nsystems.\nLimitations\nWhile the studies cited in this review provide important \ninformation on pathways associated with endometrial cancer, \nadenomyosis and endometrial cancer pathophysiology, \nthere are limitations in the approaches and study designs. \nFor example, the majority of the studies which have \nexamined EMT markers, proteases/protease inhibitors and/\nor transcription factors, many have been descriptive with \nfew studies concurrently assessing expression/localization \nand function using in vitro assays. This is extremely important \nespecially when studying the protease/protease inhibitors. \nImmunohistochemical localization and Western blot analysis \nof protease/protease inhibitors do not provide information \non function of the proteases/proteases inhibitors. Further, \n\nAljubran Y, Nothnick WB. Shared Biology Underlying Benign Endometrial Diseases and Endometrial Cancer: Current \nKnowledge and Future Prospectives. J Cell Signal. 2026;7(1):1 –20.\nJ Cell Signal. 2026\nVolume 7, Issue 1\n15\nfew studies concurrently evaluate protease and respective \nprotease inhibitor expression and/or ratio. Often both \nprotease and protease inhibitor may be expressed, and it is \nan alteration that favors net protease activity which leads to \ntissue invasion/remodeling. Additionally, greater emphasis \non patient demographics, inclusion, exclusion criteria, stage \nof disease (for endometrial cancer and endometriosis) and \ntype of lesion (for endometriosis) must be taken into account. \nThis in turn should minimize variability and heterogeneity of \nexperimental outcomes allowing for more robust data.\nFuture Studies\nFuture studies may focus on further dissecting the \nintermediates (transcription factors) associated with impaired \nsteroid signaling and altered MMP/TIMP expression. Clearly, \ncompared to endometrial cancer and endometriosis, \nadenomyosis is the least explored of the three diseases. \nAs adenomyosis diagnosis is increasing, more detailed \nexamination of this disease is warranted. When embarking \nupon future studies, it will be essential to take into account \nthe aforementioned limitations to increase experimental rigor \nand reproducibility. In turn, we anticipate this will more clearly \nalign the similarities and differences among these three \ncommon diseases in women.\nAuthors Contribution Statement\nYA and WBN wrote and edited the review article.\nConflict of Interest\nThe authors declare no conflict of interest.\nData Availability Statement\nAll data generated and included in this manuscript are \navailable upon the request of the corresponding author.\nFunding\nThere was no funding associated with the work described in \nthis review.\nReferences\n1. Setiawan VW, Yang HP , Pike MC, McCann SE, Yu H, Xiang YB, et \nal. Type I and II endometrial cancers: have they different risk \nfactors? J Clin Oncol. 2013;31(20):2607–18.\n2. Felix AS, Weissfeld JL, Stone RA, Bowser R, Chivukula M, Edwards \nRP , et al. Factors associated with Type I and Type II endometrial \ncancer. Cancer Causes Control. 2010;21(11):1851–6.\n3. Dias Da Silva I, Wuidar V, Zielonka M, Pequeux C. 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