The Molecular Basis of Adenomyosis Development

INTRODUCTION General Aspects of Adenomyosis Molecular Events in Adenomyosis Development

References Journal of Embryo Transfer 2018; 33(1): 49-54 Published online March 29, 2018 https://doi.org/10.12750/JET.2018.33.1.49 Copyright © The Korean Society of Animal Reproduction and Biotechnology. Woo Sub Yang1, Jeong Mook Lim1,2,†, and Ji Yeon Ahn2,† 1Department of Agricultural Biotechnology, Seoul National University, Seoul 151-921, Korea, 2Research Institutes of Agriculture and Life Sciences, Seoul National University, Seoul 151-921, Korea Correspondence to: Correspondence: Ji Yeon Ahn Received: December 26, 2017; Revised: January 5, 2018; Accepted: March 23, 2018 Adenomyosis is a benign gynecological disease frequently affecting women of reproductive age. It has a negative impact on the quality of life, causing bleeding disorders, dysmenorrhea, chronic pelvic pain, and infertility. However, the molecular mechanisms involved in adenomyosis development remain unclear. This paper summarizes the reports found in the MEDLINE database on the molecular mechanisms involved in the development and progression of uterine adenomyosis. The literature search included the following terms: “adenomyosis,” “adenomyoma,” “pathogenesis,” “molecular mechanisms,” and “gynecological disorders.” Only peer-reviewed, English-language journal articles were included. This review focuses on the molecular genetics, epigenetic modifications, and pivotal signaling pathways associated with adenomyosis development and progression, which will provide insights into and a better understanding of its underlying pathophysiology.

Adenomyosis, Pathogenesis, Molecular mechanisms, Gynecological disease, Adenomyoma A large number of women are affected by adenomyosis, which can adversely affect quality of life. Based on diagnostic criteria, the prevalence of the adenomyosis has been reported to range from 5% to 70% ( Adenomyosis is a benign uterine condition characterized by the presence of heterotopic epithelial cells, endometrial glands, and stroma within the myometrium, which causes thickening or swelling of the uterus ( Genetic mutations It has been suggested that genetic mutations in endometrial cells also induce adenomyosis. However, to date, the role of genetic mutations in adenomyosis has not been fully documented. Only a limited number of experimental studies confirming the mutational status of genes have been conducted to date. One study reported that mutations of estrogen receptor alpha (ERα) gene (ESR1) were found in adenomyosis ( Epithelial to mesenchymal transition (EMT) refers to the phenotypic transition of epithelial cells to mesenchymal cells, which ultimately results in the conversion of epithelial cells into cells with metastatic and invasive potential (Son & Moon, 2010). Although the transition of these cells is essential during development (Kalluri & Weinberg, 2009), it is also considered an undesirable phenomenon in relation to progression in various diseases. Reprogramming of cells by EMT mechanisms is closely linked to changes in different regulatory networks. The dysregulation of epithelial cells is caused by changes in various regulatory steps, including transcription and translation. One of the major molecular changes occurring during EMT is a reduction in CDH1 expression (Kalluri & Weinberg, 2009). Also, several reports have indicated that transcription factors such as Snail, Slug, and Twist can induce EMT in cancer ( Wnt/β -catenin signaling Several reports have described Wnt/β-catenin signaling to play an important role in EMT progression (Y. G. Notch signaling Notch signaling also contributes to adenomyosis development by EMT progression ( TGF-β signaling Epigenetic changes.Another important pathway that causes adenomyosis development is the transforming growth factor beta (TGF-β) signaling pathway ( Aberrant epigenetic events have been thought to be involved in the development of diverse diseases. Epigenetic changes involving methylation of DNA, histone modifications, and non-coding RNA have been identified in many cancers such as breast, prostate, ovarian, and endometrial cancer ( Epigenetic changes in DNA expression have been studied in the development of adenomyosis. Histone modification is a phenomenon that can alter gene function without altering DNA sequences. To form the nucleosome, DNA wraps around special proteins called histones. The overall structure of the nucleosome can be modified by different modifications including acetylation, phosphorylation, ubiquitination, and methylation of histone proteins. These modifications alter the accessibility of transcription factors to the target DNA sequences ( Gynecological diseases have recently been attracting much attention with the objective of improving the quality of life of women with these conditions. Thus, there has been a great increase in the number of molecular studies investigating the causes of gynecological diseases. Although many studies on adenomyosis have been performed, the understanding of the underlying molecular mechanisms is inadequate as the altered molecular pathways in adenomyosis are very complex and have shown different specificities in different cell types. Understanding the underlying molecular mechanisms is crucial for the development of clinical trials and for the treatment, prevention, and diagnosis of gynecological diseases involving adenomyosis. Thus, we hope that more advanced research results will accumulate in the future. - Balch C., Fang F., Matei D.E., Huang T.H., and Nephew K.P. (2009) Minireview: epigenetic changes in ovarian cancer. Endocrinology 150 : 4003-4011. - Bazot M., Darai E., Rouger J., Detchev R., Cortez A., and Uzan S. (2002) Limitations of transvaginal sonography for the diagnosis of adenomyosis, with histopathological correlation. Ultrasound Obstet. Gynecol. 20 : 605-611. - Cao J. (2014) The functional role of long non-coding RNAs and epigenetics. Biol. Proced. Online 16 : 11. - Chen J. R., Hsieh T. Y., Chen H. Y., Yeh K. Y., and Chen K. S. (2014) Absence of estrogen receptor alpha (ESR1) gene amplification in a series of breast cancers in Taiwan. Virchows Archiv : an international journal of pathology 464 : 689. - de Herreros A.G., Peiro S., Nassour M., and Savagner P. (2010) Snail family regulation and epithelial mesenchymal transitions in breast cancer progression. J. Mammary Gland Biol. Neoplasia 15 : 135-147. - Dueholm M. (2006) Transvaginal ultrasound for diagnosis of adenomyosis: a review. Best Pract. Res. Clin. Obstet. Gynaecol. 20 : 569-582. - Garavaglia E., Audrey S., Annalisa I., Stefano F., Iacopo T., Laura C., and Massimo C. (2015) Adenomyosis and its impact on women fertility. Iran. J. Reprod. Med. 13 : 327-336. - Harada T., Khine Y.M., Kaponis A., Nikellis T., Decavalas G., and Taniguchi F. (2016) The Impact of Adenomyosis on Women ?(tm)s Fertility. Obstet. Gynecol. Surv. 71 : 557-568. - He T.C., Sparks A.B., Rago C., Hermeking H., Zawel L., da Costa L.T., and Kinzler K.W. (1998) Identification of c-MYC as a target of the APC pathway. Science 281 : 1509-1512. - Jain N., and Goel S. (2012) Cystic Adenomyoma simulates uterine malformation: A diagnostic dilemma: Case report of two unusual cases. J. Hum. Reprod. Sci. 5 : 285-288. - Jiang J.F., Sun A.J., Xue W., Deng Y., and Wang Y.F. (2016) Aberrantly expressed long noncoding RNAs in the eutopic endometria of patients with uterine adenomyosis. Eur. J. Obstet. Gynecol. Reprod. Biol. 199 : 32-37. - Jiang Y.G., Luo Y., He D.L., Li X., Zhang L.L., Peng T., and Lin Y.H. (2007) Role of Wnt/beta-catenin signaling pathway in epithelial-mesenchymal transition of human prostate cancer induced by hypoxia-inducible factor-1alpha. Int. J. Urol. 14 : 1034-1039. - Kalluri R., and Weinberg R.A. (2009) The basics of epithelial-mesenchymal transition. J. Clin. Invest. 119 : 1420-1428. - Lai E.C. (2004) Notch signaling: control of cell communication and cell fate. Development 131 : 965-973. - Lamouille S., Xu J., and Derynck R. (2014) Molecular mechanisms of epithelial-mesenchymal transition. Nat. Rev. Mol. Cell Biol. 15 : 178-196. - Lee H.R., Kim T.H., and Choi K.C. (2012) Functions and physiological roles of two types of estrogen receptors, ERalpha and ERbeta, identified by estrogen receptor knockout mouse. Lab. Anim. Res. 28 : 71-76. - Liu X., and Guo S.W. (2012) Aberrant immunoreactivity of deoxyribonucleic acid methyltransferases in adenomyosis. Gynecol. Obstet. Invest. 74 : 100-108. - Liu X., Nie J., and Guo S.W. (2012) Elevated immunoreactivity against class I histone deacetylases in adenomyosis. Gynecol. Obstet. Invest. 74 : 50-55. - Marino-Ramirez L., Kann M.G., Shoemaker B.A., and Landsman D. (2005) Histone structure and nucleosome stability. Expert Rev. Proteomics 2 : 719-729. - Miyazono K. (2009) Transforming growth factor-beta signaling in epithelial-mesenchymal transition and progression of cancer. Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. 85 : 314-323. - Oehler M.K., Greschik H., Fischer D.C., Tong X., Schuele R., and Kieback D.G. (2004) Functional characterization of somatic point mutations of the human estrogen receptor alpha (hERalpha) in adenomyosis uteri. Mol. Hum. Reprod. 10 : 853-860. - Oh S.J., Shin J.H., Kim T.H., Lee H.S., Yoo J.Y., Ahn J.Y., and Jeong J.W. (2013) beta-Catenin activation contributes to the pathogenesis of adenomyosis through epithelial-mesenchymal transition. J. Pathol. 231 : 210-222. - Ota H., Igarashi S., Hatazawa J., and Tanaka T. (1998) Is adenomyosis an immune disease?. Hum. Reprod. Update 4 : 360-367. - Peric H., and Fraser I.S. (2006) The symptomatology of adenomyosis. Best Pract. Res. Clin. Obstet. Gynaecol. 20 : 547-555. - Polakis P. (2000) Wnt signaling and cancer. Genes Dev. 14 : 1837-1851. - Proctor M., and Farquhar C. (2006) Diagnosis and management of dysmenorrhoea. BMJ 332 : 1134-1138. - Qi S., Zhao X., Li M., Zhang X., Lu Z., Yang C., and Zhang N. (2015) Aberrant expression of Notch1/numb/snail signaling, an epithelial mesenchymal transition related pathway, in adenomyosis. Reproductive biology and endocrinology. RB&E 13 : 96. - Reinhold C., Tafazoli F., and Wang L. (1998) Imaging features of adenomyosis. Hum. Reprod. Update 4 : 337-349. - Sammour A., Pirwany I., Usubutun A., Arseneau J., and Tulandi T. (2002) Correlations between extent and spread of adenomyosis and clinical symptoms. Gynecol. Obstet. Invest. 54 : 213-216. - Seto E., and Yoshida M. (2014) Erasers of histone acetylation: the histone deacetylase enzymes. Cold Spring Harb. Perspect. Biol. 6 : a018713. - Shan S., Lv Q., Zhao Y., Liu C., Sun Y., Xi K., and Li C. (2015) Wnt/beta-catenin pathway is required for epithelial to mesenchymal transition in CXCL12 over expressed breast cancer cells. Int. J. Clin. Exp. Pathol. 8 : 12357-12367. - Shen M., Liu X., Zhang H., and Guo S.W. (2016) Transforming growth factor beta1 signaling coincides with epithelialmesenchymal transition and fibroblast-to-myofibroblast transdifferentiation in the development of adenomyosis in mice. Hum. Reprod. 31 : 355-369. - Shtutman M., Zhurinsky J., Simcha I., Albanese C., D'Amico M., Pestell R., and Ben-Ze'ev A. (1999) The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway. Proc. Natl. Acad. Sci. USA 96 : 5522-5527. - Son H., and Moon A. (2010) Epithelial-mesenchymal Transition and Cell Invasion. Toxicol. Res. 26 : 245-252. - Stampoliou A., Arapantoni-Dadioti P., and Pavlakis K. (2016) Epigenetic mechanisms in endometrial cancer. J. BUON 21 : 301-306. - Tamai K., Togashi K., Ito T., Morisawa N., Fujiwara T., and Koyama T. (2005) MR imaging findings of adenomyosis: correlation with histopathologic features and diagnostic pitfalls Radiographics : a review publication of the Radiological Society of North America. Inc 25 : 21-40. - Taran F.A., Stewart E.A., and Brucker S. (2013) Adenomyosis: Epidemiology, Risk Factors, Clinical Phenotype and Surgical and Interventional Alternatives to Hysterectomy. Geburtshilfe Frauenheilkd. 73 : 924-931. - Verrecchia F., and Mauviel A. (2002) Transforming growth factor-beta signaling through the Smad pathway: role in extracellular matrix gene expression and regulation. J. Invest. Dermatol. 118 : 211-215. - Wang Y., Shi J., Chai K., Ying X., and Zhou B.P. (2013) The Role of Snail in EMT and Tumorigenesis. Curr. Cancer Drug Targets 13 : 963-972. - Wang Z., Li Y., Kong D., and Sarkar F.H. (2010) The role of Notch signaling pathway in epithelial-mesenchymal transition (EMT) during development and tumor aggressiveness. Curr. Drug Targets 11 : 745-751. - Wortman M. (2008) Endometrial biopsy: a reliable method for the diagnosis of adenomyosis. J. Reprod. Med. 53 : 311-312. - Wu D.T., Bitzer M., Ju W., Mundel P., and Bottinger E.P. (2005) TGF-beta concentration specifies differential signaling profiles of growth arrest/differentiation and apoptosis in podocytes. J. Am. Soc. Nephrol. 16 : 3211-3221. - Wu Y., Sarkissyan M., and Vadgama J.V. (2015) Epigenetics in breast and prostate cancer.

Mol. Biol. 1238 : 425-466. - Xu J., Lamouille S., and Derynck R. (2009) TGF-beta-induced epithelial to mesenchymal transition. Cell Res. 19 : 156-172. - Yamamoto S., Schulze K.L., and Bellen H.J. (2014) Introduction to Notch signaling.

Mol. Biol. 1187 : 1-14. - Yazbeck C., Falcone S., Ballout A., Gauche-Cazalis C., Epelboin S., Patrat C., and Luton D. (2015). Gynecologie, obstetrique & fertilite. 43 : 665-669. - Yen C.F., Huang S.J., Lee C.L., Wang H.S., and Liao S.K. (2017) Molecular Characteristics of the Endometrium in Uterine Adenomyosis and Its Biochemical Microenvironment. Reprod. Sci. 24 : 1346-1361. - Zhou C., Zhang T., Liu F., Zhou J., Ni X., Huo R., and Shi Z. (2016) The differential expression of mRNAs and long noncoding RNAs between ectopic and eutopic endometria provides new insights into adenomyosis. Mol. Biosyst. 12 : 362-370. - Zi Z., Chapnick D.A., and Liu X. (2012) Dynamics of TGF-beta/Smad signaling. FEBS Lett. 586 : 1921-1928. Journal of Embryo Transfer 2018; 33(1): 49-54 Published online March 29, 2018 https://doi.org/10.12750/JET.2018.33.1.49 Copyright © The Korean Society of Animal Reproduction and Biotechnology. Woo Sub Yang1, Jeong Mook Lim1,2,†, and Ji Yeon Ahn2,† 1Department of Agricultural Biotechnology, Seoul National University, Seoul 151-921, Korea, 2Research Institutes of Agriculture and Life Sciences, Seoul National University, Seoul 151-921, Korea Correspondence to:Correspondence: Ji Yeon Ahn Received: December 26, 2017; Revised: January 5, 2018; Accepted: March 23, 2018 Adenomyosis is a benign gynecological disease frequently affecting women of reproductive age. It has a negative impact on the quality of life, causing bleeding disorders, dysmenorrhea, chronic pelvic pain, and infertility. However, the molecular mechanisms involved in adenomyosis development remain unclear. This paper summarizes the reports found in the MEDLINE database on the molecular mechanisms involved in the development and progression of uterine adenomyosis. The literature search included the following terms: “adenomyosis,” “adenomyoma,” “pathogenesis,” “molecular mechanisms,” and “gynecological disorders.” Only peer-reviewed, English-language journal articles were included. This review focuses on the molecular genetics, epigenetic modifications, and pivotal signaling pathways associated with adenomyosis development and progression, which will provide insights into and a better understanding of its underlying pathophysiology.

Adenomyosis, Pathogenesis, Molecular mechanisms, Gynecological disease, Adenomyoma A large number of women are affected by adenomyosis, which can adversely affect quality of life. Based on diagnostic criteria, the prevalence of the adenomyosis has been reported to range from 5% to 70% ( Adenomyosis is a benign uterine condition characterized by the presence of heterotopic epithelial cells, endometrial glands, and stroma within the myometrium, which causes thickening or swelling of the uterus ( Genetic mutations It has been suggested that genetic mutations in endometrial cells also induce adenomyosis. However, to date, the role of genetic mutations in adenomyosis has not been fully documented. Only a limited number of experimental studies confirming the mutational status of genes have been conducted to date. One study reported that mutations of estrogen receptor alpha (ERα) gene (ESR1) were found in adenomyosis ( Epithelial to mesenchymal transition (EMT) refers to the phenotypic transition of epithelial cells to mesenchymal cells, which ultimately results in the conversion of epithelial cells into cells with metastatic and invasive potential (Son & Moon, 2010). Although the transition of these cells is essential during development (Kalluri & Weinberg, 2009), it is also considered an undesirable phenomenon in relation to progression in various diseases. Reprogramming of cells by EMT mechanisms is closely linked to changes in different regulatory networks. The dysregulation of epithelial cells is caused by changes in various regulatory steps, including transcription and translation. One of the major molecular changes occurring during EMT is a reduction in CDH1 expression (Kalluri & Weinberg, 2009). Also, several reports have indicated that transcription factors such as Snail, Slug, and Twist can induce EMT in cancer ( Wnt/β -catenin signaling Several reports have described Wnt/β-catenin signaling to play an important role in EMT progression (Y. G. Notch signaling Notch signaling also contributes to adenomyosis development by EMT progression ( TGF-β signaling Epigenetic changes.Another important pathway that causes adenomyosis development is the transforming growth factor beta (TGF-β) signaling pathway ( Aberrant epigenetic events have been thought to be involved in the development of diverse diseases. Epigenetic changes involving methylation of DNA, histone modifications, and non-coding RNA have been identified in many cancers such as breast, prostate, ovarian, and endometrial cancer ( Epigenetic changes in DNA expression have been studied in the development of adenomyosis. Histone modification is a phenomenon that can alter gene function without altering DNA sequences. To form the nucleosome, DNA wraps around special proteins called histones. The overall structure of the nucleosome can be modified by different modifications including acetylation, phosphorylation, ubiquitination, and methylation of histone proteins. These modifications alter the accessibility of transcription factors to the target DNA sequences ( Gynecological diseases have recently been attracting much attention with the objective of improving the quality of life of women with these conditions. Thus, there has been a great increase in the number of molecular studies investigating the causes of gynecological diseases. Although many studies on adenomyosis have been performed, the understanding of the underlying molecular mechanisms is inadequate as the altered molecular pathways in adenomyosis are very complex and have shown different specificities in different cell types. Understanding the underlying molecular mechanisms is crucial for the development of clinical trials and for the treatment, prevention, and diagnosis of gynecological diseases involving adenomyosis. Thus, we hope that more advanced research results will accumulate in the future. - Balch C., Fang F., Matei D.E., Huang T.H., and Nephew K.P. (2009) Minireview: epigenetic changes in ovarian cancer. Endocrinology 150 : 4003-4011. - Bazot M., Darai E., Rouger J., Detchev R., Cortez A., and Uzan S. (2002) Limitations of transvaginal sonography for the diagnosis of adenomyosis, with histopathological correlation. Ultrasound Obstet. Gynecol. 20 : 605-611. - Cao J. (2014) The functional role of long non-coding RNAs and epigenetics. Biol. Proced. Online 16 : 11. - Chen J. R., Hsieh T. Y., Chen H. Y., Yeh K. Y., and Chen K. S. (2014) Absence of estrogen receptor alpha (ESR1) gene amplification in a series of breast cancers in Taiwan. Virchows Archiv : an international journal of pathology 464 : 689. - de Herreros A.G., Peiro S., Nassour M., and Savagner P. (2010) Snail family regulation and epithelial mesenchymal transitions in breast cancer progression. J. Mammary Gland Biol. Neoplasia 15 : 135-147. - Dueholm M. (2006) Transvaginal ultrasound for diagnosis of adenomyosis: a review. Best Pract. Res. Clin. Obstet. Gynaecol. 20 : 569-582. - Garavaglia E., Audrey S., Annalisa I., Stefano F., Iacopo T., Laura C., and Massimo C. (2015) Adenomyosis and its impact on women fertility. Iran. J. Reprod. Med. 13 : 327-336. - Harada T., Khine Y.M., Kaponis A., Nikellis T., Decavalas G., and Taniguchi F. (2016) The Impact of Adenomyosis on Women ?(tm)s Fertility. Obstet. Gynecol. Surv. 71 : 557-568. - He T.C., Sparks A.B., Rago C., Hermeking H., Zawel L., da Costa L.T., and Kinzler K.W. (1998) Identification of c-MYC as a target of the APC pathway. Science 281 : 1509-1512. - Jain N., and Goel S. (2012) Cystic Adenomyoma simulates uterine malformation: A diagnostic dilemma: Case report of two unusual cases. J. Hum. Reprod. Sci. 5 : 285-288. - Jiang J.F., Sun A.J., Xue W., Deng Y., and Wang Y.F. (2016) Aberrantly expressed long noncoding RNAs in the eutopic endometria of patients with uterine adenomyosis. Eur. J. Obstet. Gynecol. Reprod. Biol. 199 : 32-37. - Jiang Y.G., Luo Y., He D.L., Li X., Zhang L.L., Peng T., and Lin Y.H. (2007) Role of Wnt/beta-catenin signaling pathway in epithelial-mesenchymal transition of human prostate cancer induced by hypoxia-inducible factor-1alpha. Int. J. Urol. 14 : 1034-1039. - Kalluri R., and Weinberg R.A. (2009) The basics of epithelial-mesenchymal transition. J. Clin. Invest. 119 : 1420-1428. - Lai E.C. (2004) Notch signaling: control of cell communication and cell fate. Development 131 : 965-973. - Lamouille S., Xu J., and Derynck R. (2014) Molecular mechanisms of epithelial-mesenchymal transition. Nat. Rev. Mol. Cell Biol. 15 : 178-196. - Lee H.R., Kim T.H., and Choi K.C. (2012) Functions and physiological roles of two types of estrogen receptors, ERalpha and ERbeta, identified by estrogen receptor knockout mouse. Lab. Anim. Res. 28 : 71-76. - Liu X., and Guo S.W. (2012) Aberrant immunoreactivity of deoxyribonucleic acid methyltransferases in adenomyosis. Gynecol. Obstet. Invest. 74 : 100-108. - Liu X., Nie J., and Guo S.W. (2012) Elevated immunoreactivity against class I histone deacetylases in adenomyosis. Gynecol. Obstet. Invest. 74 : 50-55. - Marino-Ramirez L., Kann M.G., Shoemaker B.A., and Landsman D. (2005) Histone structure and nucleosome stability. Expert Rev. Proteomics 2 : 719-729. - Miyazono K. (2009) Transforming growth factor-beta signaling in epithelial-mesenchymal transition and progression of cancer. Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. 85 : 314-323. - Oehler M.K., Greschik H., Fischer D.C., Tong X., Schuele R., and Kieback D.G. (2004) Functional characterization of somatic point mutations of the human estrogen receptor alpha (hERalpha) in adenomyosis uteri. Mol. Hum. Reprod. 10 : 853-860. - Oh S.J., Shin J.H., Kim T.H., Lee H.S., Yoo J.Y., Ahn J.Y., and Jeong J.W. (2013) beta-Catenin activation contributes to the pathogenesis of adenomyosis through epithelial-mesenchymal transition. J. Pathol. 231 : 210-222. - Ota H., Igarashi S., Hatazawa J., and Tanaka T. (1998) Is adenomyosis an immune disease?. Hum. Reprod. Update 4 : 360-367. - Peric H., and Fraser I.S. (2006) The symptomatology of adenomyosis. Best Pract. Res. Clin. Obstet. Gynaecol. 20 : 547-555. - Polakis P. (2000) Wnt signaling and cancer. Genes Dev. 14 : 1837-1851. - Proctor M., and Farquhar C. (2006) Diagnosis and management of dysmenorrhoea. BMJ 332 : 1134-1138. - Qi S., Zhao X., Li M., Zhang X., Lu Z., Yang C., and Zhang N. (2015) Aberrant expression of Notch1/numb/snail signaling, an epithelial mesenchymal transition related pathway, in adenomyosis. Reproductive biology and endocrinology. RB&E 13 : 96. - Reinhold C., Tafazoli F., and Wang L. (1998) Imaging features of adenomyosis. Hum. Reprod. Update 4 : 337-349. - Sammour A., Pirwany I., Usubutun A., Arseneau J., and Tulandi T. (2002) Correlations between extent and spread of adenomyosis and clinical symptoms. Gynecol. Obstet. Invest. 54 : 213-216. - Seto E., and Yoshida M. (2014) Erasers of histone acetylation: the histone deacetylase enzymes. Cold Spring Harb. Perspect. Biol. 6 : a018713. - Shan S., Lv Q., Zhao Y., Liu C., Sun Y., Xi K., and Li C. (2015) Wnt/beta-catenin pathway is required for epithelial to mesenchymal transition in CXCL12 over expressed breast cancer cells. Int. J. Clin. Exp. Pathol. 8 : 12357-12367. - Shen M., Liu X., Zhang H., and Guo S.W. (2016) Transforming growth factor beta1 signaling coincides with epithelialmesenchymal transition and fibroblast-to-myofibroblast transdifferentiation in the development of adenomyosis in mice. Hum. Reprod. 31 : 355-369. - Shtutman M., Zhurinsky J., Simcha I., Albanese C., D'Amico M., Pestell R., and Ben-Ze'ev A. (1999) The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway. Proc. Natl. Acad. Sci. USA 96 : 5522-5527. - Son H., and Moon A. (2010) Epithelial-mesenchymal Transition and Cell Invasion. Toxicol. Res. 26 : 245-252. - Stampoliou A., Arapantoni-Dadioti P., and Pavlakis K. (2016) Epigenetic mechanisms in endometrial cancer. J. BUON 21 : 301-306. - Tamai K., Togashi K., Ito T., Morisawa N., Fujiwara T., and Koyama T. (2005) MR imaging findings of adenomyosis: correlation with histopathologic features and diagnostic pitfalls Radiographics : a review publication of the Radiological Society of North America. Inc 25 : 21-40. - Taran F.A., Stewart E.A., and Brucker S. (2013) Adenomyosis: Epidemiology, Risk Factors, Clinical Phenotype and Surgical and Interventional Alternatives to Hysterectomy. Geburtshilfe Frauenheilkd. 73 : 924-931. - Verrecchia F., and Mauviel A. (2002) Transforming growth factor-beta signaling through the Smad pathway: role in extracellular matrix gene expression and regulation. J. Invest. Dermatol. 118 : 211-215. - Wang Y., Shi J., Chai K., Ying X., and Zhou B.P. (2013) The Role of Snail in EMT and Tumorigenesis. Curr. Cancer Drug Targets 13 : 963-972. - Wang Z., Li Y., Kong D., and Sarkar F.H. (2010) The role of Notch signaling pathway in epithelial-mesenchymal transition (EMT) during development and tumor aggressiveness. Curr. Drug Targets 11 : 745-751. - Wortman M. (2008) Endometrial biopsy: a reliable method for the diagnosis of adenomyosis. J. Reprod. Med. 53 : 311-312. - Wu D.T., Bitzer M., Ju W., Mundel P., and Bottinger E.P. (2005) TGF-beta concentration specifies differential signaling profiles of growth arrest/differentiation and apoptosis in podocytes. J. Am. Soc. Nephrol. 16 : 3211-3221. - Wu Y., Sarkissyan M., and Vadgama J.V. (2015) Epigenetics in breast and prostate cancer.

Mol. Biol. 1238 : 425-466. - Xu J., Lamouille S., and Derynck R. (2009) TGF-beta-induced epithelial to mesenchymal transition. Cell Res. 19 : 156-172. - Yamamoto S., Schulze K.L., and Bellen H.J. (2014) Introduction to Notch signaling.

Mol. Biol. 1187 : 1-14. - Yazbeck C., Falcone S., Ballout A., Gauche-Cazalis C., Epelboin S., Patrat C., and Luton D. (2015). Gynecologie, obstetrique & fertilite. 43 : 665-669. - Yen C.F., Huang S.J., Lee C.L., Wang H.S., and Liao S.K. (2017) Molecular Characteristics of the Endometrium in Uterine Adenomyosis and Its Biochemical Microenvironment. Reprod. Sci. 24 : 1346-1361. - Zhou C., Zhang T., Liu F., Zhou J., Ni X., Huo R., and Shi Z. (2016) The differential expression of mRNAs and long noncoding RNAs between ectopic and eutopic endometria provides new insights into adenomyosis. Mol. Biosyst. 12 : 362-370. - Zi Z., Chapnick D.A., and Liu X. (2012) Dynamics of TGF-beta/Smad signaling. FEBS Lett. 586 : 1921-1928. | print Article | | | Export to Citation | Open Access | | Google Scholar | Send to Email | pISSN: 2671-4639 eISSN: 2671-4663