BMI1 and PTEN are key determinants of breast cancer therapy: A plausible therapeutic target in breast cancer

BMI-1 (B-lymphoma Mo-MLV insertion region 1) is a key protein partner in polycomb repressive complex 1 (PRC1) that helps in maintaining the integrity of the complex. It is also a key player in ubiquitination of histone H2A which affects gene expression pattern involved in various cellular processes such as cell proliferation, growth, DNA repair, apoptosis and senescence. In many cancers, Overexpression of BMI1 correlates with advanced stages of disease, aggressive clinicopathological behavior, poor prognosis resistance to radiation and chemotherapy. BMI1 is emerging as a key player in EMT, chemo-resistance and cancer sternness. Overexpression is observed in various cancer types such as breast, primary hepatocellular carcinoma (HCC), gastric, ovarian, head and neck, pancreatic and lung cancer. Studies have shown that experimental reduction of BMI protein level in tumor cells results in inhibition of cell proliferation, induction of apoptosis and/or senescence, and increases susceptibility to cytotoxic agents and radiation therapy. Thus, inhibition of BMI1 expression particularly in breast cancer stem cells can be used as a potential strategy for the complete elimination of tumor and to prevent disease relapse. On other hand PTEN is known to be an important tumor suppressor next to p53. In many cancers particularly in breast cancer, p53 and PTEN undergo mutations. Studies have indicated the functional and mechanistic link between the BMI-1oncoprotein and tumor suppressor PTEN in the development and progression of cancer. The current review focuses on recent findings of how oncogenicity and chemo-resistance are caused by BMI1. It also highlights the transcriptional regulation between BMI1 and PTEN that dictates the therapeutic outcome in cancers where the functional p53 is absent. Herein, we have clearly demonstrated the regulation of transcription at genomic loci of BMI1 and PTEN in cancerous tissue or cells and the possible epigenetic regulation by histone deacetylase inhibitors (HDACi) at BMI1 and PTEN loci that may provide some clue for the possible therapy against TNBC in near future.