Abstract 744: PEDF silencing a novel mechanism of antihormone resistance in breast cancer

Abstract

Abstract Despite the benefits of endocrine therapies in treating estrogen receptor alpha (ERα)-positive breast cancer, many tumors eventually become resistant. Identifying the underlying cellular and molecular mechanisms responsible for endocrine resistance remains a critical and immediate need. Pigment epithelium-derived factor (PEDF) is a multifunctional protein released by adipocytes and increased in metabolic syndrome and insulin-resistance. Moreover, PEDF belongs to the serine protease inhibitor family but does not inhibit proteases. It is a potent endogenous inhibitor of angiogenesis and a promising agent for diabetic retinopathy and potentially cancer. Previous studies have shown that PEDF expression is significantly reduced in breast cancer cells (compared to normal breast epithelium) and its reduction is associated with disease differentiation (lowest levels in poorly differentiated tumors), disease progression and poor patient outcome, however, it is not known whether PEDF plays a role in endocrine resistance. In the present study, we evaluated PEDF expression in endocrine-sensitive MCF-7, T47D, and ZR-75-1 breast cancer cells versus endocrine resistant MCF-7:5C, MCF-7:2A, and BT474 cells and found that PEDF mRNA and protein levels were dramatically reduced in the latter group of cells. In addition, tissue microarray analysis of primary tumors from patients (N=66) who subsequently developed invasive recurrence after adjuvant tamoxifen treatment revealed that expression of PEDF protein was reduced by 45% and loss of PEDF was associated with enhanced expression of phosphoSer167ERα and the receptor tyrosine kinase RET (Rearranged during Transfection). Importantly, we found that silencing endogenous PEDF in tamoxifen-sensitive MCF-7 and T47D breast cancer cells abolished their sensitivity to the inhibitory effects of tamoxifen whereas reexpression of PEDF in endocrine resistant MCF-7:5C and MCF-7:2A cells restored their sensitivity to tamoxifen and raloxifene. Furthermore, we found that reexpression of PEDF in endocrine-resistant cells significantly reduced the levels of RET, cyclin D1 and phospho-AKT, in these cells. Together, these findings suggest that PEDF silencing might be a novel mechanism for the development of endocrine resistance in breast cancer and that PEDF expression could be used as a predictive marker of endocrine sensitivity. Furthermore, these findings suggest that recombinant PEDF might be beneficial in treating patients with antihormone resistant disease with potential application in ER-negative disease. This work was supported by the NIH Career Development Grant K01CA120051 01A2 and the Hollenbach Family Fund (JLW). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 744. doi:10.1158/1538-7445.AM2011-744