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

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.
Nature medicine (Impact Factor: 28.05). 06/2012; 18(7):1102-11. DOI: 10.1038/nm.2826
Source: PubMed

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 a (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.

  • Source
    • "Possible signaling pathways in human endo- metriosis The exact role of the peritoneum in the establishment and maintenance of endometriosis has been elusive, as recently reviewed [4]. Multiple molecules and signaling pathways have been speculated to participate in the pathogenic progression of endometriosis lesions [3] [4] [5] [7], including 17β-hydroxysteroid- dehydrogenases [67] [68], steroid receptor coactivator-1 [69], adhesion/attachment/invasion proteins [70] [71], disintegrin and metalloproteinases [72], nuclear factor-kappa B [73], Wnt/β-catenin [74], and the mitogen-activated protein kinase and phosphatidylinositol 3'-kina- se/AKT [75] signaling pathways. These molecules and signaling pathways are either directly linked to estrogen synthesis and ER and PR activation or interact with ER and PR signaling pathways at different levels through signaling molecules downstream of the receptor. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Endometriosis is a complex and challenging disease that involves aberrant adhesion, growth, and progression of endometrial tissues outside of the uterine cavity, and there is evidence to suggest that estrogen plays a key role in its development and progression. Numerous in vivo clinical studies have described the ectopic expression and regulation of estrogen receptor (ER) and progesterone receptor (PR) in the different types of endometriosis compared to normal or eutopic endometrium. However, we have noticed that conflicting and contradictory results have been presented in terms of ER subtype (ERα and ERβ) and PR isoform (PRA and PRB) expression. Both ER and PR are transcription factors and ER/PR-mediated responses depend on the coordinated, opposing, and compensatory functions of ER subtypes and PR isoforms. Moreover, analysis of the uterine phenotypes of ERα/ERβ and PRA/PRB knockout mice indicates that different ER subtypes and PR isoforms mediate distinct responses to steroid hormones and play different roles in uterine function. In this review, we outline studies that have elucidated the molecules and signaling pathways that are linked to ER and/or PR signaling pathways in the development and progression of endometriosis.
    American Journal of Translational Research 01/2014; 6(2):104-113. · 3.23 Impact Factor
  • Nature medicine 07/2012; 18(7):1016-8. DOI:10.1038/nm.2855 · 28.05 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Seit der Veröffentlichung der Sequenz des menschlichen Genoms vor etwas mehr als 10 Jahren sind einige Technologien entwickelt worden, die eine Fülle an Daten zur genetischen Variabilität, zu Unterschieden in Genexpression, Epigenetik und anderen Regulationsmechanismen des Genoms generiert haben und in noch größerer Fülle generieren werden. Dies geht mit Anforderungen an klinische Studien einher, um diese an die neuen Technologien anzupassen. In der Gynäkologie und Geburtshilfe gibt es bereits einige Ergebnisse, die Einblicke in diesen sich noch entwickelnden Bereich der Wissenschaft gewähren. Diese und künftige Ansprüche an die wissenschaftliche Gemeinschaft werden im vorliegenden Beitrag dargestellt. Abstract Since the publication of the reference sequence of the human genome more than 10 years ago a variety of technologies have been developed that generate an abundance of genetic, epigenetic, gene expression and gene regulation data on a genome-wide scale. The generation of this data has had a strong influence on the methodology and design of studies and the education of scientists who want to utilize this data for the clinical practice. This article gives an overview of the current developments and the challenges that have to be addressed over the next years.
    Der Gynäkologe 09/2012; 45(9):678-683. DOI:10.1007/s00129-012-2963-3
Show more