GSE133941
Three-dimensional Oxabicycloheptene sulfonate targets the homologous recombination and repair programs through estrogen receptor a antagonism
Selective Estrogen Receptor Modulators (SERMs) are a class of structurally diverse compounds possessing unique partially agonistic and antagonistic properties and have been extensively used in treatments of hormone-responsive cancers and other diseases. Our previous studies have identified a three-dimensional SERM oxabicycloheptene sulfonate (OBHS) for estrogen receptor a (ERa), which is effective in vivo for the prevention and treatment of estrogen-dependent endometriosis. Here, using ChIP-seq and RNA-seq analysis, we found that OBHS rapidly induces genome-wide ERa occupancy behaves as a partial agonist and antagonist in ERa positive MCF-7 cells. Interestingly, OBHS downregulates the homologous recombination and repair (HRR) modules resulting in the increased DNA damage, apoptosis and cell cycle arrest, and leading to synthetic lethality with Poly (ADP-ribose) polymerase (PARP) inhibitor olaparib and genotoxic doxorubicin through blocking of ERa. Furthermore, we found that OBHS treatment results in defects of RNA polymerase II loading at the estrogen-responsive HRR genes, providing a mechanism for the regulation of HRR genes by OBHS. Together, our studies not only reveal a novel SERM OBHS which uniquely targets the homologous recombination and repair programs through ERa antagonism, but also propose a synthetic lethal strategy by combining OBHS with PARP inhibitor olaparib or genotoxic doxorubicin for ERa-responsive cancers. Overall design: Determination of the gene exression profiles by  estrogen or OBHS for 12 hours, examination of the  genome-wide ERa and Pol II occupancy after treatment of estrogen or OBHS for 1 hour.