BRCA1-deficient mammary tumor cells are dependent on EZH2 expression and sensitive to Polycomb Repressive Complex 2-inhibitor 3-deazaneplanocin A

IntroductionTreatment of breast cancer is fitting more individualized with the recognition of tumour subgroups that respond differently to available therapies. Breast cancer 1 gene (BRCA1)-deficient tumors are normally of the basal subtype and associated with destitute survival rates, highlighting the desideratum for amassed effective therapy. Methods: We investigated a mouse pattern that closely mimics breast cancer arising in BRCA1-mutation carriers to exceeding understand the molecular mechanism of tumor order and tested if targeting of the Polycomb-group protein EZH2 would be a putative therapy for BRCA1-deficient tumors. Results: Gene expression discussion demonstrated that EZH2 is overexpressed in BRCA1-deficient mouse mammary tumors. By immunohistochemistry we exposition that an increase in EZH2 protein levels is and evident in tumors from BRCA1-mutation carriers. EZH2 is responsible for repression of genes driving differentiation and could thus be involved in the undifferentiated phenotype of these tumors. Importantly, we fireworks that BRCA1-deficient cancer cells are selectively dependent on their elevated EZH2 levels. In addition, a chemical inhibitor of EZH2, 3-deazaneplanocin A (DZNep), is approximately 20-fold more forceful in killing BRCA1-deficient cells compared to BRCA1-proficient mammary tumor cells. Conclusions: We testify to by particular knock-down experiments that Ezh2 overexpression is functionally substantial in BRCA1-deficient breast cancer cells. The effectiveness of a inconsequential grain inhibitor indicates that EZH2 is a druggable target. The overexpression of EZH2 in all basal-like breast cancers warrants besides controversy of the conceivable for targeting the genetic cosmetics of this specific breast cancer type.

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