Although germline mutations in BRCA1 highly predispose women towards breast and ovarian cancer, few substantial improvements in preventing or treating such cancers have been made. Importantly, BRCA1 function is closely associated with DNA damage repair, which is required for genetic stability. Here, we examined the efficacy of radiotherapy, assessing the accumulation of genetic instabilities, in the treatment of BRCA1-associated breast cancer using a Brca1-mutant mouse model. Treatment of Brca1-mutant tumor-engrafted mice with X-rays reduced tumor progression by 27.9% compared with untreated controls. A correlation analysis of irradiation responses and biomarker profiles in tumors at baseline identified differences between responders and non-responders at the protein level (pERα, pCHK2, p53, and EpCAM) and at the SOX2 target expression level. We further demonstrated that combined treatment of Brca1-mutant mammary tumors with irradiation and AZD2281, which inhibits PARP, significantly reduced tumor progression and extended survival. Our findings enhance the understanding of DNA damage and biomarker responses in BRCA1-associated mammary tumors and provide preclinical evidence that radiotherapy with synthetic DNA damage is a potential strategy for the therapeutic management of BRCA1-associated breast cancer.

中文翻译：

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使用小鼠模型对 BRCA1 相关乳腺肿瘤放射治疗的临床前评估

尽管BRCA1的种系突变使女性高度易患乳腺癌和卵巢癌，但在预防或治疗此类癌症方面几乎没有取得实质性进展。重要的是，BRCA1 功能与 DNA 损伤修复密切相关，这是遗传稳定性所必需的。在这里，我们使用Brca1突变小鼠模型检查了放射疗法在治疗BRCA1相关乳腺癌中的疗效，评估遗传不稳定性的积累。Brca1的治疗与未经治疗的对照组相比，接受 X 射线检查的突变肿瘤移植小鼠将肿瘤进展减少了 27.9%。基线时肿瘤中照射反应和生物标志物谱的相关性分析确定了反应者和无反应者在蛋白质水平（pERα、pCHK2、p53 和 EpCAM）和 SOX2 目标表达水平上的差异。我们进一步证明了Brca1 突变型乳腺肿瘤与辐射和抑制 PARP 的 AZD2281 的联合治疗显着降低了肿瘤进展并延长了生存期。我们的研究结果增强了对BRCA1中 DNA 损伤和生物标志物反应的理解相关的乳腺肿瘤，并提供临床前证据表明具有合成 DNA 损伤的放射疗法是治疗BRCA1相关乳腺癌的潜在策略。