At the cellular level, an essential consequence of loss of BRCA1 function is impaired DNA double strand break repair. As unresolved double strand breaks will activate p53, resulting in either cell cycle arrest or apoptosis, there’s a strong choice stress on loss of p53 function in BRCA1 connected breast tumorigenesis. In addition, recent proof indicates that loss of BRCA1 inhibits differentiation into ER constructive luminal cells, which may possibly contribute to the undifferentiated phenotype. We developed a mouse model mimicking human BRCA1 defi cient breast cancer to gain insight into the molecular progres sion of BRCA1 deficient tumors and to test putative therapies. In this model, the Brca1 and p53 genes are deleted by tissue precise expression of Cre recombinase driven by the keratin 14 promoter, which is active in basal cells from the mam mary gland, which includes the stem cells.
The ensuing mam mary tumors show a solid growth pattern with pushing margins, and are extremely proliferative, poorly differentiated selleck and similar to human basal like breast cancers 2 negative. Importantly, our mouse model permits us to compare BRCA1 deficient mammary tumors mice with BRCA1 proficient handle tumors mice. Soon after comparing gene expression patterns of BRCA1 deficient mouse mammary tumors with BRCA1 proficient control tumors, we noted that Ezh2 expression was particularly high in BRCA1 deficient tumors. EZH2 is really a member of the family members of polycomb group proteins, that are epigenetic repressors that stop the expression of cell cycle inhibitors and genes needed for dif ferentiation.
We and other folks have currently observed that EZH2 overexpression is linked to aggressive tumours having a higher proliferation price as well as a poor prognosis. Inside the study presented here, we set out to identify whether or not elevated EZH2 expression also characterizes human BRCA1 deficient breast selleckchem cancer, and whether or not BRCA1 defi cient tumor cells are dependent on high EZH2 levels for their survival. This would indicate that EZH2 constitutes a therapeu tic target for BRCA1 deficient breast cancer. EZH2 is the cat alytic subunit of Polycomb Repressive Complex 2, which also includes SUZ12 and EED, and initiates gene silencing by trimethylating lysine 27 in histone H3. Tan and colleagues lately demonstrated that a smaller molecule inhibitor, three deanzaneplanocin A, proficiently lowered the protein levels of PRC2 components EZH2, SUZ12, and EED, and inhibits the related H3K27 trimethylation activity.
H3 K27me3 depletion resulted in reactivation of PRC2 silenced genes and apoptotic cell death in various cancer cell lines. The availability of a smaller molecule inhibitor which include DZNep allowed us to test whether pharma cological targeting of EZH2 function gives a selective strategy to kill BRCA1 deficient breast tumor cells.