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

Sang Jun Han, Shannon M. Hawkins, Khurshida Begum, Sung Yun Jung, Ertug Kovanci, Jun Qin, John P. Lydon, Francesco J. Demayo, Bert W. O'Malley

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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.

Original languageEnglish (US)
Pages (from-to)1102-1111
Number of pages10
JournalNature Medicine
Volume18
Issue number7
DOIs
StatePublished - Jul 1 2012

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Han, S. J., Hawkins, S. M., Begum, K., Jung, S. Y., Kovanci, E., Qin, J., Lydon, J. P., Demayo, F. J., & O'Malley, B. W. (2012). A new isoform of steroid receptor coactivator-1 is crucial for pathogenic progression of endometriosis. Nature Medicine, 18(7), 1102-1111. https://doi.org/10.1038/nm.2826