Modulation of BRCA1 mediated DNA damage repair by deregulated ER-alpha signaling in breast cancers

BRCA1 mutation carriers have a greater risk of developing cancers in hormone-responsive tissues like breasts and ovaries. However, this tissue-specific incidence of BRCA1 related cancers remains elusive. The majority of the BRCA1 mutated breast cancers exhibit typical histopathological features of high-grade tumors, with basal epithelial phenotype, classified as triple-negative molecular subtype and have a higher percentage of DNA damage and chromosomal abnormality. Though there are many studies-relating BRCA1 with ER-alpha (Estrogen receptor-alpha), it has not been reported whether E2 (Estrogen) -ER-alpha signaling can modulate the DNA repair activities of BRCA1. The present study analyzes whether deregulation of ER-alpha signaling, arising as a result of E2/ER-alpha deficiency, could impact the BRCA1 dependent DDR (DNA Damage Response) pathways, predominantly those of DNA-DSB (Double Strand break) repair and oxidative damage response. We demonstrate that E2/E2-stimulated ER-alpha can augment BRCA1 mediated high fidelity repairs like HRR (Homologous Recombination Repair) and BER (Base Excision Repair) in breast cancer cells. Conversely, a condition of ER-alpha deficiency itself or any interruption in ligand-dependent ER-alpha transactivation resulted in delayed DNA damage repair, leading to persistent activation of gamma H2AX and retention of unrepaired DNA lesions, thereby triggering tumor progression. ER-alpha deficiency not only limited the HRR in cells but also facilitated the DSB repair through error prone pathways like NHEJ (Non Homologous End Joining). ER-alpha deficiency associated persistence of DNA lesions and reduced expression of DDR proteins were validated in human mammary tumors.