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BRCA1

BRCA1

Overview

BRCA1 (breast cancer type 1 susceptibility protein) is a human tumor suppressor gene that encodes a protein essential for the maintenance of genomic stability. BRCA1 functions primarily in the repair of DNA double-strand breaks through homologous recombination repair (HRR), and it also participates in DNA damage signaling, cell-cycle checkpoint control, chromatin regulation, and transcriptional responses to genotoxic stress. Loss of BRCA1 function impairs accurate DNA repair and promotes genomic instability, which underlies its central role in hereditary breast and ovarian cancer predisposition.

Clinically, pathogenic BRCA1 variants are associated with increased lifetime risk of breast and ovarian cancer and are also relevant in other tumor types where homologous recombination deficiency influences treatment response. BRCA1 status is therefore used as a biomarker for DNA repair defects and for sensitivity to therapies such as PARP inhibitors, including olaparib and other poly(adenosine diphosphate ribose) polymerase inhibitors. In recent research, BRCA1 has also been examined in relation to tumor microenvironment features, metabolic phenotypes, and therapeutic vulnerabilities in cancers such as lung adenocarcinoma, pancreatic cancer, colorectal cancer, and breast cancer.

Focus of Latest Publications

Recent studies have continued to position BRCA1 as a key determinant of DNA repair deficiency and therapeutic sensitivity. In a review of CRISPR-mediated cancer therapies, CRISPR screening was described as having identified synthetic lethal interactions in BRCA1-/- tumors, including dependency on PARP1. This reinforces the established concept that BRCA1 loss creates a vulnerability to PARP inhibition and related DNA damage response targeting strategies.

Several studies focused on BRCA1/2-mutated breast and ovarian cancer. A multicenter Italian study reported that denosumab was associated with longer real-world progression-free survival in BRCA1/2-mutated hormone receptor-positive/HER2-negative breast cancer patients with bone metastases receiving Cdk4/6 inhibitors. The authors noted preclinical evidence suggesting that BRCA1/2-mutated tumors may rely on RANKL signaling for survival and proliferation, providing a rationale for anti-osteoporosis drug treatment in this setting. Another study examined uptake of risk-reducing mastectomy among unaffected Israeli BRCA1/BRCA2 pathogenic variant carriers, emphasizing the elevated lifetime breast cancer risk associated with pathogenic variants in these genes. A separate analysis of ipsilateral breast tumor recurrence and prognosis after breast-conserving surgery compared BRCA-positive and noncarrier patients, addressing whether BRCA1/2 pathogenic variants influence local recurrence patterns after surgery.

BRCA1 was also investigated in the context of ovarian cancer testing and treatment selection. A case series evaluating alternatives to tumor tissue for BRCA1/2 next-generation sequencing in high-grade serous ovarian carcinoma used malignant ascites as a source for testing. The study highlighted that BRCA1/2 testing is recommended at diagnosis because it affects survival when patients are treated with poly(adenosine diphosphate ribose) polymerase inhibitors. This underscores the clinical importance of BRCA1 status for selecting PARP inhibitor-based therapy.

In pancreatic cancer, a phase II trial of niraparib included patients with pathogenic variants in ATM, BRCA1, BRCA2, PALB2, and CHEK2. The study context noted that PARP inhibition has demonstrated efficacy in platinum-sensitive pancreatic cancer with germline BRCA1/2 pathogenic variants, extending the therapeutic relevance of BRCA1 beyond breast and ovarian malignancies.

Mechanistic studies also linked BRCA1 to broader DNA damage response networks. In colorectal cancer, inhibition of fatty acid synthase (FASN) enhanced chemotherapy efficacy by suppressing the DNA damage response, specifically by attenuating BRCA1 and ATM recruitment to γH2AX foci in an acetylation-dependent manner. This suggests that BRCA1 recruitment to sites of DNA damage can be modulated by metabolic interventions such as TVB-2640. In another study of hereditary breast cancers, multi-omics data revealed four disease subtypes, and homologous recombination deficiency tumors showed genomic instability including promoter hypermethylation and loss of heterozygosity at BRCA1/2. This supports the role of BRCA1 in defining genomic instability phenotypes.

BRCA1/2 were also examined outside classic hereditary breast and ovarian cancer settings. In lung adenocarcinoma, a study of the tumor microenvironment caused by BRCA1 and BRCA2 somatic mutations stated that these HRR genes are key regulators of DNA repair, while their impact on the tumor microenvironment remains unclear. This indicates growing interest in how BRCA1-associated DNA repair defects may shape immune and stromal contexts. In addition, a prospective cohort study compared impaired glucose tolerance in women with BRCA1 versus BRCA2 pathogenic or likely pathogenic variants, reflecting emerging attention to possible metabolic differences between carriers of different BRCA genes.

Across these studies, BRCA1 remains a central biomarker and mechanistic node linking homologous recombination repair, genomic instability, synthetic lethality with PARP1/PARP inhibitors, and treatment response in breast, ovarian, pancreatic, colorectal, and lung cancers.

Key Publications

  • May Molecular architecture of the tumor microenvironment caused by BRCA1 and BRCA2 somatic mutations in human lung adenocarcinoma. (eLife, 2026, PMID 42189716): "The HRR genes BRCA1/2 are key regulators of DNA repair, yet their impact on the tumor microenvironment (TME) in lung adenocarcinoma (LUAD) remains unclear."
  • May FASN Inhibition Enhances the Efficacy of Chemotherapy in Colorectal Cancer by Inhibiting the DNA Damage Response. (Cancer research, 2026, PMID 41661672): "Mechanistically, FASN inhibition decreased activation of the DDR pathway by attenuating BRCA1 and ATM recruitment to γH2AX foci in an acetylation-dependent manner."
  • May Denosumab is associated with longer real-world progression-free survival in BRCA1/2-mutated HR+ /HER2 - breast cancer patients with bone metastases receiving CDK4/6 inhibitors: A multicenter Italian study. (European journal of cancer (Oxford, England : 1990), 2026, PMID 41921366): "Preclinical evidence suggests that BRCA1/2-mutated tumors may rely on RANKL signaling for survival and proliferation."
  • May Impaired glucose tolerance in women with BRCA1 versus BRCA2 pathogenic or likely pathogenic variants: Results from a prospective cohort study. (Familial cancer, 2026, PMID 42132994): "we investigated whether the specific BRCA mutation (BRCA1 vs. BRCA2) has a differential impact on metabolism in women."
  • May Impact of BRCA1/2 pathogenic variants on ipsilateral breast tumor recurrence and prognosis following breast-conserving surgery. (Breast cancer research and treatment, 2026, PMID 42133182): "This study aimed to investigate the differences in the incidence of IBTR and prognosis between BRCA+ and noncarriers (BRCA-) after BCS."
  • May Factors influencing uptake of risk-reducing mastectomy among unaffected Israeli BRCA1/BRCA2 pathogenic variant carriers. (Familial cancer, 2026, PMID 42126651): "Women harboring pathogenic variant (PV) in the BRCA1 or BRCA2 genes (= BRCA) have an elevated lifetime risk for breast cancer (BC)."
  • May A Phase II Trial of Niraparib in Patients with Advanced Pancreatic Cancer Harboring Pathogenic Variants in ATM, BRCA1, BRCA2, PALB2, and CHEK2. (Clinical cancer research : an official journal of the American Association for Cancer Research, 2026, PMID 41686836): "PARP inhibition has demonstrated efficacy in patients with platinum-sensitive pancreatic cancer with germline BRCA1/2 pathogenic variants (PV)."
  • May Exploring alternatives to tumor tissue for BRCA1/2 next-generation sequencing testing in high-grade serous ovarian cancer: A 34-case series of malignant ascites. (Cancer cytopathology, 2026, PMID 42046206): "BRCA1/2 testing is currently recommended at diagnosis for high-grade serous ovarian carcinoma (HGSOC) because of its impact on patients' survival when treated with poly(adenosine diphosphate ribose) polymerase inhibitors."
  • Apr Delineation of the heterogeneity underlying genomic instability in hereditary breast cancers reveals four disease subtypes. (Experimental & molecular medicine, 2026, PMID 41991965): "HRD tumors exhibited genomic instability, including promoter hypermethylation and loss of heterozygosity at BRCA1/2."
  • Apr CRISPR-mediated cancer therapies: Approaches to direct tumor targeting. (Critical reviews in oncology/hematology, 2026, PMID 41833894): "CRISPR screening has identified synthetic lethal interactions, such as PARP1 dependency in BRCA1-/- tumors."
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