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BRCA1185delAG tumors may acquire therapy resistance through expression of RING-less BRCA1
Abstract:
Heterozygous germline mutations in breast cancer 1 (BRCA1) strongly predispose women to breast cancer. BRCA1 plays an important role in DNA double-strand break (DSB) repair via homologous recombination (HR), which is important for tumor suppression. Although BRCA1-deficient cells are highly sensitive to treatment with DSB-inducing agents through their HR deficiency (HRD), BRCA1-associated tumors display heterogeneous responses to platinum drugs and poly(ADP-ribose) polymerase (PARP) inhibitors in clinical trials. It is unclear whether all pathogenic BRCA1 mutations have similar effects on the response to therapy. Here, we have investigated mammary tumorigenesis and therapy sensitivity in mice carrying the Brca1185stop and Brca15382stop alleles, which respectively mimic the 2 most common BRCA1 founder mutations, BRCA1185delAG and BRCA15382insC. Both the Brca1185stop and Brca15382stop mutations predisposed animals to mammary tumors, but Brca1185stop tumors responded markedly worse to HRD-targeted therapy than did Brca15382stop tumors. Mice expressing Brca1185stop mutations also developed therapy resistance more rapidly than did mice expressing Brca15382stop. We determined that both murine Brca1185stop tumors and human BRCA1185delAG breast cancer cells expressed a really interesting new gene domain-less (RING-less) BRCA1 protein that mediated resistance to HRD-targeted therapies. Together, these results suggest that expression of RING-less BRCA1 may serve as a marker to predict poor response to DSB-inducing therapy in human cancer patients.
Insights
Germline mutations in breast cancer 1 (BRCA1) predispose to breast cancer. Certain BRCA1 mutations, like RING-less BRCA1, can cause resistance to DNA double-strand break (DSB) therapies, impacting treatment response.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- Germline mutations in breast cancer 1 (BRCA1) significantly increase breast cancer risk.
- BRCA1 is crucial for DNA double-strand break (DSB) repair through homologous recombination (HR), a key tumor suppressor mechanism.
- BRCA1-deficient tumors are sensitive to DSB-inducing agents, yet clinical responses to platinum drugs and PARP inhibitors are variable.
Purpose of the Study:
- To investigate how specific BRCA1 mutations affect mammary tumorigenesis and sensitivity to homologous recombination deficiency (HRD)-targeted therapy.
- To compare the impact of two common BRCA1 founder mutations (BRCA1185delAG and BRCA15382insC) on tumor development and treatment response in mice.
- To identify molecular mechanisms underlying differential therapy responses in BRCA1-mutated cancers.
Main Methods:
- Utilized mouse models carrying Brca1185stop and Brca15382stop alleles, mimicking human BRCA1 founder mutations.
- Assessed mammary tumorigenesis and response to HRD-targeted therapy in these mouse models.
- Analyzed the expression and function of BRCA1 protein in murine tumors and human breast cancer cells.
Main Results:
- Both Brca1185stop and Brca15382stop mutations predisposed to mammary tumors.
- Brca1185stop tumors exhibited significantly worse response and faster resistance development to HRD-targeted therapy compared to Brca15382stop tumors.
- Murine Brca1185stop tumors and human BRCA1185delAG cells expressed a RING-less BRCA1 protein, mediating resistance to HRD-targeted therapies.
Conclusions:
- The specific nature of BRCA1 mutations influences tumor response to DNA repair-targeted therapies.
- Expression of a RING-less BRCA1 protein is associated with poor response to DSB-inducing therapies.
- RING-less BRCA1 may serve as a predictive biomarker for treatment resistance in human cancers.
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