Loss of PEDF: A Novel Mechanism of Antihormone Resistance in Breast Cancer.

摘要

Our laboratory has identified a novel protein called pigment epithelium derived factor (PEDF) that appears to be suppressed/silenced in endocrine resistant breast cancer. Specifically, we have found that PEDF protein level is significantly reduced in tamoxifen-resistant breast tumors and breast cancer cells. PEDF is a multifunctional glycoprotein that is known to have potent antiangiogenic activities and has recently been shown to have antitumor properties. However, its role in endocrine resistance has never been studied. We hypothesize that loss of PEDF expression in breast cancer is a novel mechanism for the development of endocrine resistance. Hence, the objective of our study is to characterize the role of PEDF in endocrine resistance and elucidate its mechanism of action in endocrine resistance using cell and animal models. We propose three specific aims: (1) Elucidate the mechanism(s) by which loss of PEDF confers resistance to endocrine therapy and its reexpression resensitizes resistant cells to the inhibitory effects of antihormones; (2) Study the role of ERa in PEDF regulation in endocrine sensitive and endocrine resistant breast cancer cells; and (3) Determine the effect of PEDF overexpression on endocrine resistant breast cancer cell growth in athymic mice and elucidate its mechanism of action in vivo.