Abstract P2-05-06: Nuclear STING localization induces chemoresistance in breast cancer

Abstract

Abstract Efficient DNA damage repair (DDR) is crucial for a cell as aberrant repair can create deleterious mutations and genomic instability while unrepaired damage leads to cell apoptosis. Cells with altered DDR are more inclined to develop a variety of diseases, including cancers Cancer therapies including radiotherapy and chemotherapy rely on double strand break (DBS) formation to drive the killing of rapidly cycling tumor cells. As efficient DNA repair pathways can enable tumor cells to survive treatment-induced DNA damage, the identification of new actors participating in efficient DDR will help design alternative therapeutic approaches. Here we report that the well-known DNA sensor of innate immunity Stimulator of Interferon Genes (STING) is directly involved in the modulation of DSB repair efficiency in breast cancer cells. STING partly resides at the inner membrane of the nucleus where it interacts with core proteins of DNA-damage complexes and promotes its assembly with chromatin. STING silencing decreases DNA repair and cell viability, while STING overexpression protects cancer cells from genotoxic treatment. STING involvement in DNA repair is independent of the canonical STING-triggered pro-inflammatory response. In line with this observation, while overall STING expression level is positively correlated with favorable outcome in breast cancer patients, high STING expression in breast and ovarian cancer patients treated with adjuvant chemotherapy is associated with poor prognosis. This newly-identified function of STING elucidates a cell autonomous tumor-promoting mechanism complementary and independent from its well-documented role in tumor immunosurveillance. Citation Format: Laura Cheradame, Chiara Guerrera, Jean-Gabriel Judde, Vincent Goffin, Stefano Cairo. Nuclear STING localization induces chemoresistance in breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-05-06.