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Orthotopic Transplantation of Breast Tumors as Preclinical Models for Breast Cancer
Published on: May 18, 2020
Preclinical evaluation of radiation therapy of BRCA1-associated mammary tumors using a mouse model
Eun Ju Cho1, Jong Kwang Kim1, Hye Jung Baek1
1Research Institute, National Cancer Center, Goyang, 10408, Korea.
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.
Insights
Radiotherapy effectively reduced BRCA1-associated breast cancer progression in mice. Combining X-ray treatment with PARP inhibition (AZD2281) further improved outcomes, offering a potential therapeutic strategy.
Area of Science:
- Oncology
- Genetics
- Radiotherapy
Background:
- Germline mutations in BRCA1 increase breast and ovarian cancer risk, yet effective prevention and treatment strategies remain limited.
- BRCA1 protein is crucial for DNA damage repair and maintaining genetic stability.
- Understanding treatment responses in BRCA1-mutant cancers is vital for improving patient outcomes.
Purpose of the Study:
- To evaluate the efficacy of radiotherapy in treating BRCA1-associated breast cancer using a mouse model.
- To identify biomarkers predicting response to radiotherapy in BRCA1-mutant tumors.
- To investigate the combined effect of radiotherapy and PARP inhibition (AZD2281) on tumor progression and survival.
Main Methods:
- Utilized a Brca1-mutant mouse model engrafted with mammary tumors.
- Administered X-ray irradiation to assess tumor progression and genetic instability.
- Performed correlation analysis of protein and gene expression biomarkers in relation to irradiation response.
- Evaluated the combined efficacy of irradiation and AZD2281 treatment.
Main Results:
- X-ray treatment reduced tumor progression by 27.9% in Brca1-mutant mice compared to controls.
- Biomarker analysis identified differences between responders and non-responders at the protein (pERα, pCHK2, p53, EpCAM) and SOX2 target expression levels.
- Combined irradiation and AZD2281 treatment significantly reduced tumor progression and extended survival.
Conclusions:
- Radiotherapy shows efficacy in managing BRCA1-associated breast cancer.
- Specific biomarkers can predict response to radiotherapy, aiding personalized treatment approaches.
- Combination therapy with radiotherapy and PARP inhibitors presents a promising strategy for BRCA1-mutant breast cancer.
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