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A new isoform of steroid receptor coactivator-1 is crucial for pathogenic progression of endometriosis

Nature Medicine volume 18, pages 1102–1111 (2012)Cite this article

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Abstract

Endometriosis is considered to be an estrogen-dependent inflammatory disease, but its etiology is unclear. Thus far, a mechanistic role for steroid receptor coactivators (SRCs) in the progression of endometriosis has not been elucidated. An SRC-1–null mouse model reveals that the mouse SRC-1 gene has an essential role in endometriosis progression. Notably, a previously unidentified 70-kDa SRC-1 proteolytic isoform is highly elevated both in the endometriotic tissue of mice with surgically induced endometriosis and in endometriotic stromal cells biopsied from patients with endometriosis compared to normal endometrium. Tnf−/− and Mmp9−/− mice with surgically induced endometriosis showed that activation of tumor necrosis factor α (TNF-α)–induced matrix metallopeptidase 9 (MMP9) activity mediates formation of the 70-kDa SRC-1 C-terminal isoform in endometriotic mouse tissue. In contrast to full-length SRC-1, the endometriotic 70-kDa SRC-1 C-terminal fragment prevents TNF-α–mediated apoptosis in human endometrial epithelial cells and causes the epithelial-mesenchymal transition and the invasion of human endometrial cells that are hallmarks of progressive endometriosis. Collectively, the newly identified TNF-α–MMP9–SRC-1 isoform functional axis promotes pathogenic progression of endometriosis.

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Figure 1: The endometriotic 70-kDa SRC-1 isoform.
Figure 2: The mouse SRC-1 gene has an essential role in the progression of endometriosis.
Figure 3: The endometriotic SRC-1 isoform was the SRC-1 C-terminal fragment.
Figure 4: The TNF-α–MMP9 functional axis had an essential role in the progression of endometriosis and the formation of the endometriotic SRC-1 isoform in endometriotic tissue.
Figure 5: MMP9 directly cleaved human SRC-1 at P790-M791 in vitro and in vivo.
Figure 6: Endometriotic SRC-1 C-terminal isoform prevented TNF-α–induced cell death and increased EMT to improve the invasive capacity of human endometrial epithelial cells.

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References

  1. Bulun, S.E. Endometriosis. N. Engl. J. Med. 360, 268–279 (2009).

    Article  CAS  Google Scholar 

  2. Missmer, S.A. & Cramer, D.W. The epidemiology of endometriosis. Obstet. Gynecol. Clin. North Am. 30, 1–19, vii (2003).

    Article  Google Scholar 

  3. Meldrum, D.R. et al. “Medical oophorectomy” using a long-acting GNRH agonist—a possible new approach to the treatment of endometriosis. J. Clin. Endocrinol. Metab. 54, 1081–1083 (1982).

    Article  CAS  Google Scholar 

  4. Noble, L.S., Simpson, E.R., Johns, A. & Bulun, S.E. Aromatase expression in endometriosis. J. Clin. Endocrinol. Metab. 81, 174–179 (1996).

    CAS  Google Scholar 

  5. Fedele, L., Bianchi, S., Zanconato, G., Tozzi, L. & Raffaelli, R. Gonadotropin-releasing hormone agonist treatment for endometriosis of the rectovaginal septum. Am. J. Obstet. Gynecol. 183, 1462–1467 (2000).

    Article  CAS  Google Scholar 

  6. Imai, A., Takagi, A. & Tamaya, T. Gonadotropin-releasing hormone analog repairs reduced endometrial cell apoptosis in endometriosis in vitro. Am. J. Obstet. Gynecol. 182, 1142–1146 (2000).

    Article  CAS  Google Scholar 

  7. Simsa, P. et al. Selective estrogen-receptor modulators and aromatase inhibitors: promising new medical therapies for endometriosis? Womens Health (Lond. Engl.) 3, 617–628 (2007).

    Article  CAS  Google Scholar 

  8. Fujimoto, J., Hirose, R., Sakaguchi, H. & Tamaya, T. Expression of oestrogen receptor-α and -β in ovarian endometriomata. Mol. Hum. Reprod. 5, 742–747 (1999).

    Article  CAS  Google Scholar 

  9. Harris, H.A., Bruner-Tran, K.L., Zhang, X., Osteen, K.G. & Lyttle, C.R. A selective estrogen receptor-β agonist causes lesion regression in an experimentally induced model of endometriosis. Hum. Reprod. 20, 936–941 (2005).

    Article  CAS  Google Scholar 

  10. Xiu-li, W., Wen-jun, C., Hui-hua, D., Su-ping, H. & Shi-long, F. ERB-041, a selective ER β agonist, inhibits iNOS production in LPS-activated peritoneal macrophages of endometriosis via suppression of NF-κB activation. Mol. Immunol. 46, 2413–2418 (2009).

    Article  Google Scholar 

  11. Bedaiwy, M.A. et al. Prediction of endometriosis with serum and peritoneal fluid markers: a prospective controlled trial. Hum. Reprod. 17, 426–431 (2002).

    Article  CAS  Google Scholar 

  12. Berkkanoglu, M. & Arici, A. Immunology and endometriosis. Am. J. Reprod. Immunol. 50, 48–59 (2003).

    Article  Google Scholar 

  13. Falconer, H. et al. Treatment with anti-TNF monoclonal antibody (c5N) reduces the extent of induced endometriosis in the baboon. Hum. Reprod. 21, 1856–1862 (2006).

    Article  CAS  Google Scholar 

  14. Efstathiou, J.A. et al. Nonsteroidal antiinflammatory drugs differentially suppress endometriosis in a murine model. Fertil. Steril. 83, 171–181 (2005).

    Article  CAS  Google Scholar 

  15. Osteen, K.G., Yeaman, G.R. & Bruner-Tran, K.L. Matrix metalloproteinases and endometriosis. Semin. Reprod. Med. 21, 155–164 (2003).

    Article  CAS  Google Scholar 

  16. Nap, A.W., Dunselman, G.A.J. & de Goeij, A.F.P.M. Evers, J.L.H. & Groothuis, P.G. Inhibiting MMP activity prevents the development of endometriosis in the chicken chorioallantoic membrane model. Hum. Reprod. 19, 2180–2187 (2004).

    Article  CAS  Google Scholar 

  17. Lonard, D.M., Lanz, R.B. & O'Malley, B.W. Nuclear receptor coregulators and human disease. Endocr. Rev. 28, 575–587 (2007).

    Article  CAS  Google Scholar 

  18. Suzuki, A. et al. Immunohistochemical detection of steroid receptor cofactors in ovarian endometriosis: involvement of down-regulated SRC-1 expression in the limited growth activity of the endometriotic epithelium. Virchows Arch. 456, 433–441 (2010).

    Article  CAS  Google Scholar 

  19. Kumagami, A., Ito, A., Yoshida-Komiya, H., Fujimori, K. & Sato, A. Expression patterns of the steroid receptor coactivator family in human ovarian endometriosis. J. Obstet. Gynaecol. Res. 37, 1269–1276 (2011).

    Article  Google Scholar 

  20. Fang, Z. et al. Intact progesterone receptors are essential to counteract the proliferative effect of estradiol in a genetically engineered mouse model of endometriosis. Fertil. Steril. 82, 673–678 (2004).

    Article  CAS  Google Scholar 

  21. Hirata, T. et al. Interleukin-17F increases the secretion of interleukin-8 and the expression of cyclooxygenase 2 in endometriosis. Fertil. Steril. 96, 113–117 (2011).

    Article  CAS  Google Scholar 

  22. Matsuzaki, S. et al. Expression of estrogen receptor α and β in peritoneal and ovarian endometriosis. Fertil. Steril. 75, 1198–1205 (2001).

    Article  CAS  Google Scholar 

  23. Bergqvist, A., Bruse, C., Carlberg, M. & Carlstrom, K. Interleukin 1β, interleukin-6, and tumor necrosis factor-α in endometriotic tissue and in endometrium. Fertil. Steril. 75, 489–495 (2001).

    Article  CAS  Google Scholar 

  24. Chishima, F. et al. Increased expression of cyclooxygenase-2 in local lesions of endometriosis patients. Am. J. Reprod. Immunol. 48, 50–56 (2002).

    Article  Google Scholar 

  25. Wang, H.B. et al. [Expression of vascular endothelial growth factor receptors in the ectopic and eutopic endometrium of women with endometriosis]. Zhonghua Yi Xue Za Zhi 85, 1555–1559 (2005).

    CAS  Google Scholar 

  26. Banu, S.K., Starzinski-Powitz, A., Speights, V.O., Burghardt, R.C. & Arosh, J.A. Induction of peritoneal endometriosis in nude mice with use of human immortalized endometriosis epithelial and stromal cells: a potential experimental tool to study molecular pathogenesis of endometriosis in humans. Fertil. Steril. 91, 2199–2209 (2009).

    Article  Google Scholar 

  27. Hombach-Klonisch, S. et al. Regulation of functional steroid receptors and ligand-induced responses in telomerase-immortalized human endometrial epithelial cells. J. Mol. Endocrinol. 34, 517–534 (2005).

    Article  CAS  Google Scholar 

  28. Krikun, G. et al. A novel immortalized human endometrial stromal cell line with normal progestational response. Endocrinology 145, 2291–2296 (2004).

    Article  CAS  Google Scholar 

  29. Rubel, C.A., Jeong, J.W., Tsai, S.Y., Lydon, J.P. & Demayo, F.J. Epithelial-stromal interaction and progesterone receptors in the mouse uterus. Semin. Reprod. Med. 28, 27–35 (2010).

    Article  CAS  Google Scholar 

  30. Grund, E.M. et al. Tumor necrosis factor-α regulates inflammatory and mesenchymal responses via mitogen-activated protein kinase kinase, p38, and nuclear factor κB in human endometriotic epithelial cells. Mol. Pharmacol. 73, 1394–1404 (2008).

    Article  CAS  Google Scholar 

  31. Sanz, A.B., Santamaria, B., Ruiz-Ortega, M., Egido, J. & Ortiz, A. Mechanisms of renal apoptosis in health and disease. J. Am. Soc. Nephrol. 19, 1634–1642 (2008).

    Article  CAS  Google Scholar 

  32. Overton, C., Fernandez-Shaw, S., Hicks, B., Barlow, D. & Starkey, P. Peritoneal fluid cytokines and the relationship with endometriosis and pain. Hum. Reprod. 11, 380–386 (1996).

    Article  CAS  Google Scholar 

  33. Shakiba, K. & Falcone, T. Tumour necrosis factor-α blockers: potential limitations in the management of advanced endometriosis? A case report. Hum. Reprod. 21, 2417–2420 (2006).

    Article  Google Scholar 

  34. Leite, R.S., Brown, A.G. & Strauss Iii, J.F. Tumor necrosis factor-α suppresses the expression of steroid receptor coactivator-1 and -2: a possible mechanism contributing to changes in steroid hormone responsiveness. FASEB J. 18, 1418–1420 (2004).

    Article  CAS  Google Scholar 

  35. Pino, M. et al. Association between MMP1 and MMP9 activities and ICAM1 cleavage induced by tumor necrosis factor in stromal cell cultures from eutopic endometria of women with endometriosis. Reproduction 138, 837–847 (2009).

    Article  CAS  Google Scholar 

  36. Vilen, S.-T. et al. Intracellular co-localization of trypsin-2 and matrix metalloprotease-9: possible proteolytic cascade of trypsin-2, MMP-9 and enterokinase in carcinoma. Exp. Cell Res. 314, 914–926 (2008).

    Article  CAS  Google Scholar 

  37. Dufour, A., Zucker, S., Sampson, N.S., Kuscu, C. & Cao, J. Role of matrix metalloproteinase-9 (MMP-9) dimers in cell migration: design of inhibitory peptides. J. Biol. Chem. 285, 35944–35956 (2010).

    Article  CAS  Google Scholar 

  38. Scott, K.A. et al. TNF-α regulates epithelial expression of MMP-9 and integrin αvβ6 during tumour promotion. A role for TNF-α in keratinocyte migration? Oncogene 23, 6954–6966 (2004).

    Article  CAS  Google Scholar 

  39. Zhang, H. et al. Endometriotic stromal cells lose the ability to regulate cell-survival signaling in endometrial epithelial cells in vitro. Mol. Hum. Reprod. 15, 653–663 (2009).

    Article  CAS  Google Scholar 

  40. Islimye, M. et al. Regression of endometrial autografts in a rat model of endometriosis treated with etanercept. Eur. J. Obstet. Gynecol. Reprod. Biol. 159, 184–189 (2011).

    Article  CAS  Google Scholar 

  41. Xu, J. et al. Partial hormone resistance in mice with disruption of the steroid receptor coactivator-1 (SRC-1) gene. Science 279, 1922–1925 (1998).

    Article  CAS  Google Scholar 

  42. Cummings, A.M. & Metcalf, J.L. Induction of endometriosis in mice: a new model sensitive to estrogen. Reprod. Toxicol. 9, 233–238 (1995).

    Article  CAS  Google Scholar 

  43. Han, S.J. et al. Dynamic cell type specificity of SRC-1 coactivator in modulating uterine progesterone receptor function in mice. Mol. Cell. Biol. 25, 8150–8165 (2005).

    Article  CAS  Google Scholar 

  44. Hawkins, S.M. et al. Functional microRNA involved in endometriosis. Mol. Endocrinol. 25, 821–832 (2011).

    Article  CAS  Google Scholar 

  45. Wu, R.C. et al. Regulation of SRC-3 (pCIP/ACTR/AIB-1/RAC-3/TRAM-1) coactivator activity by I κ B kinase. Mol. Cell. Biol. 22, 3549–3561 (2002).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank C.J. Lockwood (Department of Obstetrics, Gynecology and Reproductive Science and Department of Genetics, Yale University School of Medicine) and T. Klonisch (Department of Human Anatomy and Cell Science, University of Manitoba) for providing immortalized human endometrial stromal and epithelial cells for this work. We thank M.J. Park for her technical support in animal experiments. We also thank the US National Institutes of Health–designated Diabetes and Endocrinology Research Center and the Proteomics Core in the Dan L. Duncan Cancer Center at Baylor College of Medicine for supporting this work. This work was supported by grants from the US National Institute of Diabetes and Digestive and Kidney Diseases (U54HD0077495 and 5K12HD050128 to S.M.H., U54HD007495 to F.J.D., R01 HD08188 to B.W.O. and a U54HD007495 pilot grant to S.J.H.) and a grant from the US National Cancer Institute (R01 CA077030 to J.P.L.).

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Authors and Affiliations

  1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA

    Sang Jun Han, Khurshida Begum, Sung Yun Jung, Jun Qin, John P Lydon, Francesco J DeMayo & Bert W O'Malley

  2. Department of Obstetrics, Baylor College of Medicine, Houston, Texas, USA

    Shannon M Hawkins & Ertug Kovanci

  3. Department of Gynecology, Baylor College of Medicine, Houston, Texas, USA

    Shannon M Hawkins & Ertug Kovanci

  4. Department of Biochemistry and Molecular Biology, Center for Molecular Discovery, Verna and Marrs McLean, Baylor College of Medicine, Houston, Texas, USA

    Sung Yun Jung & Jun Qin

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Contributions

S.J.H. led the project and designed and performed most of experiments. K.B., S.Y.J. and J.Q. provided technical expertise. S.M.H. and E.K. provided primary normal HESCs and primary human endometriotic stromal cells. J.P.L. and F.J.D. provided intellectual inputs. B.W.O. supervised the entire project. S.J.H. and B.W.O. wrote the manuscript.

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Correspondence to Bert W O'Malley.

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Han, S., Hawkins, S., Begum, K. et al. A new isoform of steroid receptor coactivator-1 is crucial for pathogenic progression of endometriosis. Nat Med 18, 1102–1111 (2012). https://doi.org/10.1038/nm.2826

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