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 BRCA1/2 loss. In high grade serous ovarian cancer (HGSOC) these markers are mutually exclusive, and potentially 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, unlike in HGSOC. This was not associated with amplification to increase cyclin E1 gene expression. Instead, BRCA1 loss stabilised cyclin E1 during the cell cycle. Using siRNA we showed that BRCA1 loss leads to cell cycle stabilisation of cyclin E1 by reducing phospho-cyclin E1 T62, and conversely the overexpression of BRCA1 increased phospho-T62. Mutation of cyclin E1 T62 to alanine increased cyclin E1 stability, and contributed to increased survival in Paclitaxel. We then found that patients with high cyclin E1/BRCA1 mutation in the BLBC cohort had decreased phospho-T62.
Since cyclin E1/Cdk2 protects cells from DNA damage and cyclin E1 is elevated in BRCA1 null cancers, we hypothesised that CDK2 inhibition would sensitise these cancers to PARP inhibition. CDK2 inhibition induced DNA damage and synergised with the PARP inhibitors in BRCA1 mutated cell lines. Treatment of BLBC PDX models with combination PARP and CDK2 inhibition led to tumour 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.