Epigenetic Targeting to Deplete Cytostatic Breast cancer cells under Endocrine Therapy

Abstract

Approximately 70% of breast cancer are hormone receptor-positive, which express estrogen receptors (ER) and are dependent on estrogen to grow. Hormonal therapies using selective estrogen receptor modulators, such as tamoxifen, are frequently used to treat ER+ breast cancer. Tamoxifen treatments have shown efficacy in managing ER+ breast cancer, but approximately 30% of patients relapse even after prolonged remission. Tamoxifen can suppress the growth of ER+ breast cancer cells and arrest them in a cytostatic state, but the cytostatic cancer cells require continual maintenance and constitute a persistent reservoir from which resistant cell clones and relapses can emerge. Depleting such persistent cytostatic cancer cells could improve treatment outcomes but targeting cancer cells in non-proliferating state has been elusive. Our laboratory has recently performed a small molecule screen with an epigenetic compound library on an ER+ breast cancer cell line and identified histone deacetylases (HDACs) as candidates for targeting persistent cytostatic cancer cells under hormonal therapy. In this thesis, I worked with other members in the laboratory to determine the efficacy and selectivity of clinical-grade HDAC inhibitors in depleting persistent cytostatic breast cancer cells under tamoxifen treatments and explore the underlying targeting mechanisms. We showed a dose-dependent efficacy of multiple HDAC inhibitors in inducing apoptosis in different tamoxifen-mediated cytostatic breast cancer cell models. Importantly, HDAC inhibition showed low toxicity in normal non-proliferating mammary cells, highlighting the selectivity of the targeting approach. On-going mechanistic study suggested that HDAC inhibition in the tamoxifen-induced cytostatic cancer cells promotes the accumulation of acetylated histone and induce apoptosis by upregulating the proapoptotic protein BIM at both mRNA and protein levels. Together, this work underscores a therapeutic opportunity for depleting persistent cytostatic breast cancer cells under hormonal therapy and established HDACs as candidates for targeting.