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 ApcMin/+ 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;ApcMin/+ 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;ApcMin/+ 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;ApcMin/+ 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.

中文翻译：

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APC 丢失会影响 DNA 损伤修复，导致乳腺癌细胞对阿霉素产生耐药性。


化疗耐药是美国癌症相关死亡的主要原因之一。三阴性乳腺癌 (TNBC) 是一种缺乏用于靶向治疗的已知乳腺癌受体的亚型，依赖化疗作为标准治疗。 70% 的散发性乳腺癌中，腺瘤性结肠息肉病 (APC) 肿瘤抑制基因发生突变或高甲基化，这些散发性乳腺癌具有类似于 TNBC 亚型的 APC 缺陷型肿瘤。使用来自 ApcMin/+ 小鼠模型的乳腺肿瘤细胞与多瘤中 T 抗原 (PyMT) 转基因模型杂交，我们之前表明 APC 损失降低了对阿霉素 (DOX) 的敏感性。了解化疗耐药的分子基础对于开发新的治疗方法以最终改善患者的治疗效果至关重要。耐药性可以通过不同的方法引起，但在这里我们重点关注 DOX 治疗的 DNA 修复反应。我们发现，与 MMTV-PyMT;Apc+/+ 细胞相比，24 小时 DOX 处理后，MMTV-PyMT;ApcMin/+ 细胞的 DNA 损伤减少。这种损害的减少首先在治疗后 24 小时内观察到，并持续到药物恢复的 24 小时内。与对照细胞相比，MMTV-PyMT;ApcMin/+ 细胞中 DNA 损伤反应途径（ATM、Chk1 和 Chk2）的激活在 24 小时 DOX 处理时减少，但在较早的时间点表现出激活。使用靶向 DNA 损伤修复激酶（ATM、ATR 和 DNA-PK）的抑制剂，我们发现 ATM 和 DNA-PK 抑制增加了 DOX 诱导的 MMTV-PyMT;ApcMin/+ 细胞凋亡。在目前的工作中，我们证明 APC 损失通过减少 DNA 损伤反应来赋予抵抗力，这种反应可以通过 DNA 修复抑制来减弱，这表明 DNA 修复抑制作为联合疗法的潜在临床用途。