Abstract 4880: PELP1 localization as a biomarker for early mammary carcinogenesis and response to tamoxifen chemoprevention.

Abstract

Abstract Progress in breast cancer prevention is currently limited by our lack of biological markers to identify which high-risk women will progress to develop breast cancer and which women will respond to chemoprevention therapies, such as tamoxifen (Tam). While Tam has proven to be effective for breast cancer chemoprevention, Tam therapy only reduces the risk of developing breast cancer by approximately 50%. Therefore, identification of biomarkers is essential to determine which women will benefit from Tam chemoprevention. We have been studying the role of PELP1 in early mammary carcinogenesis and response to Tam chemoprevention. PELP1 subcellular localization is primarily nuclear in normal mammary epithelium, but it has been shown to be localized to the cytoplasm of <50% of PELP1 positive breast tumors. Targeting PELP1 to the cytoplasm leads to activation of non-genomic signaling to ERK1/2 and AKT and promotes Tam-resistance breast cancer cells. Additionally, it has been shown that transgenic mice expressing cytoplasmic PELP1 develop mammary gland hyperplasia. We have developed human mammary epithelial cell (HMEC) lines that express either vector control, wild-type PELP1 or a mutant of PELP1 in which the nuclear localization sequence has been mutated and the protein is predominately cytoplasmic (PELP1-cyto). Data generated using these cells lines indicates that PELP1-cyto, but not wild-type PELP1, promotes Tam-resistance. Our data also suggest that Tam treatment results in non-apoptotic death of HMECs. We found that Tam treatment induces the expression of LC3, an autophagy marker, and that Tam-induced LC3 expression is blocked in HMECs expressing PELP1-cyto. Together these data suggest that Tam-induced autophagy may be the mechanism of death in the HMEC cell lines and that cytoplasmic PELP1 may inhibit autophagic death. The objective of our current research is to determine if cytoplasmic PELP1 expression promotes expression of a novel gene signature that predicts response to Tam chemoprevention. We are currently testing models of early mammary carcinogenesis (pre-stasis, post-stasis, and immortal) for their response to Tam in the presence and absence of cytoplasmic PELP1. Microarray analysis will be performed on RNA from cell line that represents the earliest point in mammary carcinogenesis in which we see an effect of PELP1 expression. We expect that these studies will provide us with gene signatures that can predict cytoplasmic PELP1 expression and Tam resistance in early mammary carcinogenesis. Gene signatures will then be validated using existing gene array databases. These studies have the potential to lead to additional targets for chemoprevention and benefit women who are resistant to Tam chemoprevention. Citation Format: Julie Hanson Ostrander, Brian Girard, Tarah M. Regan-Anderson, Siya Lem, Victoria L. Seewaldt. PELP1 localization as a biomarker for early mammary carcinogenesis and response to tamoxifen chemoprevention. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4880. doi:10.1158/1538-7445.AM2013-4880