Preclinical evaluation of radiation therapy of BRCA1-associated mammary tumors using a mouse model

Abstract

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.

Comparison of mutation landscapes of pretreatment versus recurrent squamous cell carcinoma of the oral cavity: The possible mechanism of resistance to standard treatment

“…The unique finding of DNA repair gene mutations in tumors with a good response to radiotherapy or chemo‐radiotherapy was supported in a previous study in a mouse model of engrafted BRCA1 ‐deficient tumors.The mouse models showed hypersensitivity to radiation. 46 The finding of mutant DNA repair genes may be one factor to indicate one of the prediction methods for patients who may benefit from standard treatment as shown in Figure 4C . In agreement with our result, cancer cells containing DNA repair gene defects were shown to be hypersensitive to platinum‐based chemotherapy, such as cisplatin.…”