LAUSR

Breast cancer is the most common cancer diagnosis and second leading cause of cancer related deaths among women in the United States. This poor prognosis is in part due to the high rates of resistance. In particular, resistance to anti-HER2-based therapy remains a clinical challenge for women with breast cancer suggesting that better treatment strategies are needed. Results demonstrate that resistance to trastuzumab correlates with lower PKC activity compared to trastuzumab sensitive breast cancer cells, suggesting that downregulation of PKC activity may contribute to trastuzumab resistance. The exact mechanism by which PKCs contribute to trastuzumab resistance is not well understood. Here, we hypothesized that activation of PKCs could prevent trastuzumab resistance and thus inhibit the survival and recurrence of HER2+ breast cancer. Our results show that in two distinct trastuzumab-resistant cell lines (HCC1954 and BT474), activation of PKC by the phorbol ester TPA inhibits both proliferation of bulk cells and survival of cancer stem cells (CSC) as assessed by mammosphere formation. Further, treatment using a pharmacological PKC inhibitor (GF109203X) almost completely rescued the anti-proliferative and anti-CSC survival effects of TPA in two distinct trastuzumab-resistant cell lines. Measurement of PKC isoforms at the transcript and protein levels showed that PKCδ was overexpressed in the resistant cell line compared to the sensitive cell line. PKCδ depletion using a siRNA prevented the anti-proliferative and anti-CSC survival effects of TPA, suggesting that PKCδ was the target of TPA activation in trastuzumab resistant cells. TPA-mediated activation of PKCδ was found to cause G2/M cell cycle arrest, almost complete inhibition of AKT phosphorylation at serine 473, and decreased expression of the CSC marker, ALDH1A1. These results suggest that phorbol ester-mediated activation of PKCδ could be a novel therapeutic strategy for HER2+ breast cancer that is resistant to trastuzumab-based therapy. Citation Format: Debra L. Wyatt, Andrei Zlobin, Emily Ma, Mitchell F. Denning, Clodia Osipo. PKCδ as a novel target for HER2-positive, trastuzumab resistant breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1831.