Abstract B21: Improved efficacy of mitochondrial disrupting agents upon inhibition of autophagy in a mouse model of BRCA1-deficient breast cancer

Abstract

Abstract Breast cancer is a heterogeneous disease, and stratification of patients is fundamental to the success of treatment modalities. Breast tumors deficient in BRCA1 are mostly associated with basal-like breast cancers, and targeted therapeutics for this disease subtype are still lacking. In order to address whether autophagy inhibition will be effective in BRCA1-deficient mammary tumors, we generated mice with conditional deletion of an essential autophagy gene FIP200 along with Brca1 and Trp53, through utilization of the K14-Cre transgene. We found that FIP200 deletion suppressed tumorigenesis in the BRCA1-deficient model when compared to wild-type and heterozygous FIP200 controls. However, in contrast to previous studies in the MMTV-PyMT model, tumor growth and the distribution of histologic subtypes were not affected by loss of FIP200. Interestingly, loss of FIP200 decreased mitochondrial mass and oxidative respiratory capacity of these tumor cells, along with a decrease in the phosphorylation of mTOR substrates and transcript levels of genes involved in mitochondrial biogenesis. Importantly, we observed an increased sensitivity to mitochondrial disrupting agents upon loss of FIP200. Consequently, our data showed that combination of an autophagy inhibitor, Spautin-1, along with a mitochondrial complex I inhibitor, metformin, was more effective in limiting oxidative respiratory capacity, colony-forming ability, and tumor growth. Altogether, our results indicate that inhibition of autophagy can increase the benefits of metformin treatment in BRCA1-deficient breast cancers. Citation Format: Syn Kok Yeo, Ritama Paul, Michael Haas, Chenran Wang, Jun-Lin Guan. Improved efficacy of mitochondrial disrupting agents upon inhibition of autophagy in a mouse model of BRCA1-deficient breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B21.