Abstract IA19: Regulation of 53BP1 in BRCA1-deficient cells: Why vitamin D matters and how disparities in vitamin D levels could promote aggressive TNBC in women of color

Abstract

Abstract Breast cancer is the leading cause of cancer death in women worldwide. BRCA1-deficient and triple-negative breast cancers (TNBC) are particularly aggressive, strike younger, Hispanic and African American women, and are most difficult to treat. These tumors exhibit DNA repair defects, making them vulnerable to DNA damaging therapies. Currently, the most promising therapeutic agents are poly(ADP-ribose) polymerase inhibitors (PARPi), which render cells already deficient in DNA repair, with an unbearable load of DNA damage. Excitement about PARPi has been fueled by clinical trials showing that these compounds, either as single agents or in combination with chemotherapy, have very encouraging outcomes in BRCA1-related and TNBC and with minimal toxicity. However, a significant fraction of these cancers acquire resistance to PARPi. Understanding the molecular mechanisms that confer PARPi resistance will have a big therapeutic impact. Elegant studies demonstrated that loss of the DNA repair factor 53BP1 contributes to progression of BRCA1-deficient and TNBC and to their resistance to PARPi. Thus, raising the levels of 53BP1 in these tumors could represent a new therapeutic strategy. Our team identified a new pathway modulating the levels of 53BP1, which could be exploited to stabilize protein levels. We found that BRCA1-deficient cells activate the degradation of 53BP1 by the protease cathepsin-L (CTSL), and that CTSL inhibition by vitamin D stabilizes 53BP1, reduces proliferation, and increases PARPi and radiation sensitivity. Our studies in human breast tumors also suggest that deficiencies in vitamin D/vitamin D receptor (VDR) axis, more prevalent in women of color, could underlie the activation of CTSL-mediated degradation of 53BP1 in BRCA1-deficient and TNBC. Our current studies are testing the ability of vitamin D treatment to reduce the growth of BRCA1-deficient and TNBC cells, as well as their resistance to PARPi, providing a novel modality of treatment for these cancer patients. Citation Format: Susana Gonzalo. Regulation of 53BP1 in BRCA1-deficient cells: Why vitamin D matters and how disparities in vitamin D levels could promote aggressive TNBC in women of color. [abstract]. In: Proceedings of the Seventh AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 9-12, 2014; San Antonio, TX. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2015;24(10 Suppl):Abstract nr IA19.