Abstract
Recent clinical trials demonstrating the efficacy of poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of BRCA1-deficient breast cancer have provided support for the 'synthetic lethal' concept of targeted cancer therapeutics. A new study provides further preclinical validation of this concept by demonstrating that BRCA1-deficient mouse mammary tumor cells are selectively sensitive to an inhibitor of the polycomb gene EZH2. The development of polycomb gene inhibitors may provide a novel approach to selectively exploit the molecular alterations in BRCA1-deficient breast tumors.
Highlights
EZH2 is a subunit of the large ‘polycomb repressor complex 2’, which initiates gene silencing by trimethylating lysine 27 in histone H3 (H3-K27 ME3)
PRC2 and PRC1 polycomb genes function in a ‘linear fashion’ in normal development, it has been suggested that their overexpression may have different functional consequences for breast tumorigenesis [9]
Liu and colleagues [10] demonstrated that BRCA1 regulates the differentiation of estrogen receptor (ER)-negative breast stem cells into ER-positive luminal progenitors
Summary
EZH2 is a subunit of the large ‘polycomb repressor complex 2’, which initiates gene silencing by trimethylating lysine 27 in histone H3 (H3-K27 ME3). Both EZH2 and Bmi-1 have been shown to play important roles in regulating the self-renewal and differentiation of normal stem cells. Recent studies have demonstrated that, in addition to its wellknown role in DNA repair, BRCA1 plays an important role in breast development.
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