Triple-negative breast cancer is characterized by aggressive tumours whose cells lack oestrogen and progesterone receptors and do not over-express HER2. It accounts for approximately 10-15% of breast cancer cases. We sought to generate a cellular model of chemotherapy drug resistance for this type of disease to provide the tools for the development of new therapies. Doxorubicin is a component of some chemotherapy regimes used to treat this form of cancer but resistance preventing disease eradication frequently occurs, mainly due to over-expression of drug transporters such as P-glycoprotein. CALDOX cells were generated by exposure of CAL51 to doxorubicin. Resistance to doxorubicin did not involve drug transporters, as the both parental and resistant cells accumulated doxorubicin to comparable levels. CALDOX cells had slower proliferation rate and an extended G1 cell cycle stage than the parental line, mainly due to an intrinsic activation of CDNK1 (p21), but this cell cycle block was not involved in the mechanism of resistance. CALDOX cells had reduced levels of TOP2A (topoisomerase IIα) and were cross resistant to the topoisomerase II inhibitors etoposide and mitoxantrone. CALDOX cells showed collateral sensitivity to carmustine due to the lack of O⁶-methylguanine-DNA-methyltransferase (MGMT) expression, related to the hypermethylation of its promoter. The collateral sensitivity of CALDOX cells to carmustine provides the rationale to evaluate MGMT promoter methylation status to design better therapeutic strategies for triple negative breast cancer.

译文

三阴性乳腺癌的特征是侵袭性肿瘤,其细胞缺乏雌激素和孕激素受体,并且不会过度表达HER2。它约占乳腺癌病例的10-15%。我们试图为这种类型的疾病生成化学疗法抗药性的细胞模型,以提供开发新疗法的工具。阿霉素是一些用于治疗这种形式癌症的化学治疗方案的组成部分,但经常会出现防止根除疾病的抗药性,这主要是由于药物转运蛋白(例如P-糖蛋白)的过度表达所致。通过将CAL51暴露于阿霉素可产生CALDOX细胞。对阿霉素的耐药性不涉及药物转运蛋白,因为亲代细胞和耐药细胞都将阿霉素蓄积到可比较的水平。 CALDOX细胞比亲代细胞具有较低的增殖速率和延长的G1细胞周期阶段,这主要是由于CDNK1(p21)的内在激活,但该细胞周期阻滞并不参与耐药机制。 CALDOX细胞的TOP2A(拓扑异构酶IIα)水平降低,并且对拓扑异构酶II抑制剂依托泊苷和米托蒽醌具有交叉耐药性。由于缺少与启动子的高甲基化有关的O⁶-甲基鸟嘌呤-DNA-甲基转移酶(MGMT)表达,CALDOX细胞对卡莫司汀表现出了附带敏感性。 CALDOX细胞对卡莫司汀的附带敏感性为评估MGMT启动子甲基化状态提供了理论依据,从而为三阴性乳腺癌设计更好的治疗策略。

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