Abstract
Basal-like breast cancers (BLBC) are aggressive breast cancers that respond poorly to targeted therapies and chemotherapies. In order to define therapeutically targetable subsets of BLBC we examined two markers: cyclin E1 and BRCA1 loss. In high grade serous ovarian cancer (HGSOC) these markers are mutually exclusive, and define therapeutic subsets. We tested the same hypothesis for BLBC. Using a BLBC cohort enriched for BRCA1 loss, we identified convergence between BRCA1 loss and high cyclin E1 protein expression, in contrast to HGSOC in which CCNE1 amplification drives increased cyclin E1. In cell lines, BRCA1 loss was associated with stabilized cyclin E1 during the cell cycle, and BRCA1 siRNA led to increased cyclin E1 in association with reduced phospho-cyclin E1 T62. Mutation of cyclin E1 T62 to alanine increased cyclin E1 stability. We showed that tumors with high cyclin E1/BRCA1 mutation in the BLBC cohort also had decreased phospho-T62, supporting this hypothesis. Since cyclin E1/CDK2 protects cells from DNA damage and cyclin E1 is elevated in BRCA1 mutant cancers, we hypothesized that CDK2 inhibition would sensitize these cancers to PARP inhibition. CDK2 inhibition induced DNA damage and synergized with PARP inhibitors to reduce cell viability in cell lines with homologous recombination deficiency, including BRCA1 mutated cell lines. Treatment of BRCA1 mutant BLBC patient-derived xenograft models with combination PARP and CDK2 inhibition led to tumor regression and increased survival. We conclude that BRCA1 status and high cyclin E1 have potential as predictive biomarkers to dictate the therapeutic use of combination CDK inhibitors/PARP inhibitors in BLBC.
Highlights
Breast cancer with BRCA1 mutation most often manifests as basal-like breast cancer (BLBC)[1], which presents difficulties for treatment as these cancers present at an earlier age, at a high grade, and with greater tumor burden
The poly (ADP-ribose) polymerase (PARP) inhibitors olaparib and talazoparib were recently FDA approved for use as monotherapy in patients with metastatic germline BRCA1/2-mutated breast cancer based on significant improvement in progression-free survival compared to chemotherapy[31]
We here find that BRCA1 loss reduces the turnover of cyclin E1 thereby increasing proliferation and survival, providing a new therapeutic opportunity to enhance the synthetic lethality of PARP inhibitors by co-targeting the cyclin E1/cyclin-dependent kinase 2 (CDK2) axis
Summary
Breast cancer with BRCA1 mutation most often manifests as basal-like breast cancer (BLBC)[1], which presents difficulties for treatment as these cancers present at an earlier age, at a high grade, and with greater tumor burden. Alterations to BRCA1 are important founder mutations for breast cancer[5], and notably, more than 70% of BRCA1 mutation carriers develop early-onset BLBC based on gene expression profiling[6]. A previous report identified that BLBCs from patients with germline BRCA1 mutation was associated with high cyclin E1 protein expression[9]. Cyclin E1 is a cell cycle regulatory protein that activates cyclin-dependent kinase 2 (CDK2), and whose gain can promote both increased proliferation and genomic instability in cancer cells, and is frequently elevated in BLBC10
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