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

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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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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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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