Abstract LB-040: SIRT1 requires for mammary stem cell self-renewal and maintenance

Abstract

Abstract In spite of the many advances in cancer diagnosis and treatment, breast cancer remains a devastating disease among women worldwide. Although the critical role of estrogen (E2) in breast cancer has been unequivocally established and antiestrogens have been successfully used to treat this disease, there are about 2.6 million women in the United States who are continue to suffer from this disease. Further, approximately 80% of breast cancers are initially E2-dependent and respond well to antiestrogens, but many of them develop resistance and become unresponsive to antiestrogen therapy. Despite through investigation, the molecular mechanisms underlying this loss of responsiveness to antiestrogen therapy and the precise signaling molecules that impart E2-induced mitogenic signaling have not been fully understood. This gap in knowledge constitutes a significant impediment in effective prevention and treatment of this disease. Thus, the purpose of this study is to identify the precise signaling processes that impart E2 signaling and the molecular mechanisms underlying the resistance to hormonal therapy in breast cancer. In this study, we found that SIRT1, a type III histone deacetylase (HDAC), plays a critical role in E2-induced tumor growth as well as chemoresistance in human breast cancer cells. Functional inactivation of this gene abolished E2-induced tumor growth and made it more susceptible to hormonal- and chemotherapy-induced growth arrest and apoptosis. Additionally, our study showed that mammary stem-cells require Sirt1 for self-renewal and maintenance in the undifferentiated-state. Interestingly, mammary gland specific Sirt1-knockdown significantly reduced breast tumor growth and metastasis in syngeneic and genetically engineered mouse (GEM) models of breast cancer by limiting breast cancer stem cell (BCSC) self-renewal. RNA-seq analysis provided evidence that Sirt1 deletion is associated with significantly reduced expression of genes involved in BCSC self-renewal, tumor growth and metastasis, and drug resistance. Treatment of GEM mouse models of breast cancer with SIRT1 inhibitor reduced tumor growth with increased overall survival. Altogether, our study provides strong evidence that SIRT1 is a key regulator of E2-induced tumor growth signaling, and a potential modifier of drug resistance. Functional inactivation of this gene will effectively block mammary tumor development and circumvent drug resistance, which in turn could significantly increase the disease-free survival. Citation Format: Utkarsh Parwal, Parth Patel, Sabarish Ramachandran, Rajneesh Pathania, Allison Bridges, Pragya Rajpurohit, Puttur D. Prasad, Muthusamy Thangaraju. SIRT1 requires for mammary stem cell self-renewal and maintenance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-040.