Three-dimensional Oxabicycloheptene sulfonate targets the homologous recombination and repair programs through estrogen receptor α 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 α (ERα), 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 ERα occupancy behaves as a partial agonist and antagonist in ERα 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 ERα. 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 ERα antagonism, but also propose a synthetic lethal strategy by combining OBHS with PARP inhibitor olaparib or genotoxic doxorubicin for ERα-responsive cancers.