Abstract PS16-23: Elucidating the role of APC resulting in doxorubicin resistance in breast cancer

Abstract

Abstract Chemoresistance is a leading cause of breast cancer related deaths. Therefore, understanding the molecularbasis for chemoresistance is essential for novel therapeutic advancement improving patient outcome. TheAdenomatous Polyposis Coli (APC) tumor suppressor is lost in up to 70% of sporadic breast cancer; however,little is known about how APC loss contributes to chemoresistance. Using mammary tumor cells isolated fromthe Apc Min/+ mouse crossed to the Polyoma middle T antigen (PyMT) transgenic model, we werethe first to show that APC loss decreased doxorubicin (DOX) induced apoptosis. Therefore, we investigatedthe mechanisms contributing to DOX resistance with APC loss to identify combination therapy options. DOX, acommonly used chemotherapeutic in breast cancer, inhibits topoisomerase IIa (Topo IIa), causing doublestranded breaks (DSBs), the most lethal form of DNA damage, and APC has been shown to affect Topo IIaactivity. DSB repair is mediated through HRR (homologous recombination repair) or NHEJ (nonhomologousend joining), which are regulated by the repair serine/threonine kinases: ataxia telangiectasia mutated (ATM)or ataxia telangiectasia and Rad3 related (ATR), but only NHEJ activates DNA-dependent protein kinase(DNA-PK). We hypothesized that APC loss prevents DOX-mediated apoptosis through alterations in HRR andNHEJ. To investigate the effect of APC loss on DNA damage repair pathways, we monitored damagerecognition pathways after 24-hour DOX treatment. The MMTV-PyMT;Apc Min/+ cells exhibited decreaseddamage as measured by γH2AX expression and comet assay. We also observed decreased ATMphosphorylation in MMTV-PyMT;Apc Min/+ following DOX treatment compared to control. Decreasedphosphorylation of Chk1 and Chk2 was also observed in DOX-treated MMTV-PyMT;Apc Min/+ cells. Using theATM inhibitor (KU55933) or the DNA-PK inhibitor (NU7441), we observed increased DOX-induced apoptosis inMMTV-PyMT;Apc Min/+ cells. These data suggest enhanced DNA repair in MMTV-PyMT;Apc Min/+ cells and will beconfirmed by measuring repair efficiency via reporter plasmids. In addition, knowing that APC affects activitiesby Topo IIa, we measured the amount of Topo IIa: DNA cleavage complexes following DOX treatment.Taken together, APC loss mediates DOX resistance via increasing DNA repair demonstrating the potential useof combination therapy to overcome chemoresistance. Citation Format: Jeni Prosperi, Casey Stefanski. Elucidating the role of APC resulting in doxorubicin resistance in breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS16-23.