Abstract B027: Evaluation of dnaja2:A target for chemotherapy sensitization of cancer cells

Abstract

Abstract Breast cancer is the second most common cause of death from cancer in women in the United States. The disease accounts for 1 in 3 of new female cancers annually. Triple-negative breast cancer (TNBC) is the most aggressive and fatal subtype of breast cancer. TNBC is estrogen receptor-negative, progesterone receptor-negative, and HER2-negative providing fewer treatment options and resulting in worse prognosis. There are a variety of chemotherapy drugs used to treat TNBC but they may cause serious side effects which limit their use. Our laboratory has investigated the pathways that protect cells from anthracyclines, a commonly used chemotherapy agent. Through a genetic screening in the yeast S. cerevisiae, we identified YDJ1, which encodes for a gene involved in the heat-shock response pathway, that when inactivated rendered cells over 100-fold more sensitive to doxorubicin. YDJ1 is a homolog of the human gene DNAJA2 (DnaJ homolog subfamily A member 2). The protein encoded by this gene belongs to the DNAJ/HSP40 family of proteins, which regulate molecular chaperone activity by stimulating ATPase activity of Hsp70 promoting the folding of denatured proteins. We hypothesize that DNAJA2 protects cells from anthracycline exposure. To evaluate the role of DNAJA2 in the sensitivity of cancer cells exposed to doxorubicin, we knocked down DNAJA2 in the TNBC cell line MDA-MB-231 using a lentivirus-based shRNA. Cells were made stably transfected by continued selection with puromycin. Resulting knockdown cells show significant reduction of DNAJA2 protein. In addition, the cells also show accumulation of ROS, decreased cell mobility and decreased resistance to anticancer agents such as doxorubicin. Additional phenotypes are currently under investigation, as well as the interaction of the other members of the DNAJA family of proteins. We hope that our data contributes to the development of protocols to sensitize cancer cells to chemotherapy. Funding provided by the Florida-California Cancer Research, Education and Engagement (CaRE2) Health Equity Center. Tissue Modeling Core. U54CA233396, subproject 6636 Citation Format: Feng Bai, Hernan Flores Rozas. Evaluation of dnaja2:A target for chemotherapy sensitization of cancer cells [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B027.