Estrogen receptor alpha (ERα) driven trans-regulation of mitotic checkpoint complex (MCC) components affects the clinical outcome of breast cancer

Hormone receptors (HR), namely estrogen receptor (ER) and progesterone receptor (PR), are prevalent in most malignant tumors. Although previous literature provided clues for ER in regulating mitosis and ploidy status in breast cancer (BC) cells, reports on the mitotic regulators being the targets of HR are sparse. To delve deeper into ERs impact on mitotic execution, our study focuses on examining its transcriptional activity on the core mitotic checkpoint complex (MCC) components, which are involved in ploidy maintenance. The expression of the core MCC components (Bub3, Mad2, and BubR1) was analyzed by quantitative-PCR and immunohistochemistry in breast tumors and adjacent normal tissues from the cancer genome atlas-breast invasive carcinoma collection (TCGA BRCA) dataset and in a prospective cohort of Eastern Indian breast cancer affected individuals. The preliminary data from these cohorts indicated an influence of ER on the two MCC components, namely Mad2 and BubR1. Subsequently, luciferase reporter assays and chromatin immunoprecipitation were performed which revealed that ER promotes transcriptional activation of MAD2 and BUB1B through direct recruitment on these promoters, showing affects in mitotic outcome. Interestingly, the ectopic introduction of ER, in an HR-ve breast cancer line, MDA-MB-231, significantly reduced the percent aneuploidy. Moreover, we found that overexpression of MAD2 and BUB1B is associated with poorer survival in HR-positive (HR+ve) patients in both cohorts. Our findings provide insights into the specific role of ER-mediated transcriptional regulation of mitosis and ploidy outcome. Targeting the deregulated MCC components thus offers translational potential for the therapeutic management of breast cancer.