Research Institute, National Cancer Center, Goyang, 10408, Korea.
Proton Therapy Center, National Cancer Center Hospital, Goyang, 10408, Korea.
Int J Biol Sci. 2021 Jan 31;17(3):689-701. doi: 10.7150/ijbs.53667. eCollection 2021.
Although germline mutations in 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 -associated breast cancer using a -mutant mouse model. Treatment of -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 -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 -associated mammary tumors and provide preclinical evidence that radiotherapy with synthetic DNA damage is a potential strategy for the therapeutic management of -associated breast cancer.
虽然种系突变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治疗在治疗 BRCA1 相关乳腺癌中的疗效，评估了遗传不稳定性的积累。与未治疗的对照组相比，用 X 射线治疗 BRCA1 突变肿瘤移植小鼠可使肿瘤进展减少 27.9%。对基线时照射反应和肿瘤生物标志物谱的相关性分析，在蛋白水平（pERα、pCHK2、p53 和 EpCAM）和 SOX2 靶基因表达水平上鉴定出了应答者和非应答者之间的差异。我们进一步证明，用抑制 PARP 的 AZD2281 联合照射治疗 BRCA1 突变型乳腺肿瘤可显著降低肿瘤进展并延长生存期。我们的研究结果增强了对 BRCA1 相关乳腺肿瘤中 DNA 损伤和生物标志物反应的理解，并提供了临床前证据，表明放射治疗与合成 DNA 损伤是治疗 BRCA1 相关乳腺癌的潜在策略。
