Does Cytoplasmic PELP1 Predict Resistance To Tamoxifen Chemoprevention?

While Tamoxifen (Tam) has proven to be effective as a breast cancer prevention agent, Tam therapy only reduces the risk of developing breast cancer by ~50% in high risk women. Therefore, identification of biomarkers is essential to determine which women will benefit from Tam prevention. Recent studies suggest that rapid non-classical hormone signaling may play an important role in normal mammary gland homeostasis through stimulation of extra nuclear targets and co-activator recruitment. We observe in breast cytology specimens from high-risk women that ER expression is elevated in only 20% of mammary atypia and low ER expression in mammary atypia does not predict resistance to Tam prevention. We hypothesize that in women with mammary atypia, rapid non-classic signaling may play an important role regulating response to Tam prevention. PELP1 is a transcriptional nuclear activator of ER-signaling. Cytoplasmic expression of PELP1 in breast cancer cells triggers contitutive activation of AKT and results in Tam-resistance. Further, Dr. Seewaldt's laboratory has demonstrated that Tam promotes apoptosis through the coordinated regulation of AKT- phosphorylation. The objective of my current research is to determine if PELP1 localization predicts response to Tam. Here, I aim to test the hypothesis that cytoplasmic PELP1 promotes Tam-resistance, in part, through constitutive activation of AKT. The following Aims are proposed: 1) Does cytoplasmic localization of PELP1 in HMECs promote Tam-resistance through constitutive activation of Akt? 2) Does cytoplasmic PELP1 localization in atypical RPFNA cytological samples from high-risk women predict dysregulated AKT? 3) Does cytoplasmic PELP1 in atypical RPFNA predict cytological resistance to Tam prevention?