Chemoresistance is one of the leading causes of cancer-related deaths in the United States. Triple negative breast cancer (TNBC), a subtype lacking the known breast cancer receptors used for targeted therapy, is reliant on chemotherapy as the standard of care. The Adenomatous Polyposis Coli (APC) tumor suppressor is mutated or hypermethylated in 70% of sporadic breast cancers with APC-deficient tumors resembling the TNBC subtype. Using mammary tumor cells from the Apc^Min/+ mouse model crossed to the Polyoma middle T antigen (PyMT) transgenic model, we previously showed that APC loss decreased sensitivity to doxorubicin (DOX). Understanding the molecular basis for chemoresistance is essential for the advancement of novel therapeutic approaches to ultimately improve patient outcomes. Resistance can be caused via different methods, but here we focus on the DNA repair response with DOX treatment. We show that MMTV-PyMT;Apc^Min/+ cells have decreased DNA damage following 24 hour DOX treatment compared to MMTV-PyMT;Apc^+/+ cells. This decreased damage is first observed 24 hours post-treatment and continues throughout 24 hours of drug recovery. Activation of DNA damage response pathways (ATM, Chk1, and Chk2) are decreased at 24 hours DOX-treatment in MMTV-PyMT;Apc^Min/+ cells compared to control cells, but show activation at earlier time points. Using inhibitors that target DNA damage repair kinases (ATM, ATR, and DNA-PK), we showed that ATM and DNA-PK inhibition increased DOX-induced apoptosis in the MMTV-PyMT;Apc^Min/+ cells. In the current work, we demonstrated that APC loss imparts resistance through decreased DNA damage response, which can be attenuated through DNA repair inhibition, suggesting the potential clinical use of DNA repair inhibitions as combination therapy.

化学抗药性是美国癌症相关死亡的主要原因之一。三阴性乳腺癌（TNBC）是一种缺乏已知的用于靶向治疗的乳腺癌受体的亚型，它依赖化学疗法作为护理标准。的结肠腺瘤样息肉（APC）肿瘤抑制被突变或在散发性乳腺癌的70％甲基化与APC-缺陷肿瘤形似TNBC亚型。使用Apc ^{Min / +中的}乳腺肿瘤细胞小鼠模型与Polyoma中T抗原（PyMT）转基因模型杂交后，我们先前表明APC丢失会降低对阿霉素（DOX）的敏感性。理解化学抗性的分子基础对于推进新型治疗方法以最终改善患者预后至关重要。可以通过不同的方法引起抗药性，但是在这里，我们主要关注DOX处理对DNA的修复反应。我们展示了MMTV-PyMT；与MMTV-PyMT相比，经过24小时的DOX处理后，Apc ^{Min / +}细胞的DNA损伤减少；APC ^{+ / +}细胞。这种减少的损害首先在治疗后24小时观察到，并在药物恢复的整个24小时内持续发生。DNA损伤反应途径（ATM，Chk1和Chk2）的激活在MMTV-PyMT中的DOX处理24小时时降低；与对照细胞相比，Apc ^{Min / +}细胞具有激活作用，但在更早的时间点显示激活。使用针对DNA损伤修复激酶的抑制剂（ATM，ATR和DNA-PK），我们发现ATM和DNA-PK抑制作用增加了DOX诱导的MMTV-PyMT细胞凋亡。Apc ^{Min / +}细胞。在当前的工作中，我们证明了APC的丧失通过降低的DNA损伤反应赋予了抵抗力，而DNA损伤的抑制作用可以通过DNA修复的抑制作用减弱，这暗示了DNA修复抑制作用作为联合治疗的潜在临床应用。