Abstract 545: Autocrine growth regulation by PEDF is mediated by ovarian steroid hormones: Implications in the pathogenesis of endometrial carcinoma

Abstract

Abstract The angiogenic inhibitor and neurotrophic factor, pigment epithelium-derived factor (PEDF) was first shown in the eye and is now shown to be expressed in a number of tissues and to function in apoptosis and growth inhibition. The importance of PEDF in growth regulation of the endometrium is reflected in PEDF null mice, which develop endometrial hyperplasia. Therefore, we hypothesized that PEDF is decreased in human endometrial carcinoma with loss of growth inhibition. We show by immunostaining (n=44) that PEDF expression is decreased in both stromal and epithelial cells in atypical endometrial hyperplasia (AEH), the precursor to type I endometrial carcinoma (ECA; 80% of all ECAs) and ECA. Whereas PEDF is highly expressed by primary endometrial epithelial cells (EECs) and stromal cells, ECA cells synthesize less protein and stromal cells isolated from malignant endometrium (cancer associated fibroblasts; CAFs) synthesize 80% less PEDF mRNA (n=35) by quantitative real time PCR and less PEDF protein. In addition, whereas exogenous recombinant PEDF inhibits proliferation of ECA cell lines (e.g. HEC-1B by 40%; peak response at 4nM), PEDF antibodies and PEDF siRNA stimulate proliferation suggesting PEDF inhibits cell proliferation in an autocrine manner in the endometrium. Estrogen (E2) stimulates and progesterone (Pg) inhibits proliferation of the endometrium in a cyclical manner. Due to these hormonal growth regulatory effects, E2 induces AEH and Type I ECA and Pg is a successful therapeutic agent for these diseases. Therefore, we further hypothesized that E2 decreases PEDF causing dysreglated growth and conversely, that Pg might inhibit growth by increasing PEDF. Indeed, we show that treatment of the ECA cell lines, HEC-1A, HEC-1B, KLE and primary EECs with E2 decreased PEDF mRNA and protein expression, which was blocked by the estrogen receptor (ER) antagonist, ICI 182,780. In direct contrast, Pg increased PEDF mRNA and protein, which was blocked by the antagonist, RU486. It is notable that the PEDF promoter contains two putative PREs and one ERE thereby justifying these responses. Taken together, our data implicate PEDF as an autocrine hormone-regulated inhibitor of endometrial growth and suggest that the E2-driven decrease in PEDF leads to dysregulated endometrial growth as an important molecular target in the pathogenesis of type I ECA. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 545. doi:1538-7445.AM2012-545