Functional And Mechanistic Studies Of A Novel Oxabicycloheptene Sulfonate Selective Estrogen Receptor Modulator

Breast cancer is the most commonly diagnosed cancer diagnosed and the leading cause of cancer death among women all over the world.About 70% of breast cancers are estrogen receptor ?(ER?)positive.ER? and estrogen signal pathway are reported to be involved in the stimulation of proliferation and survival of breast cancer cells.Anti-estrogen endocrine therapy is the first-line adjuvant treatment for patients with ER?-positive breast cancer,among which,selective estrogen receptor modulators(SERMs)have been intensively studied over the past decades and induced good outcomes in clinical trials.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(such as breast cancer,ovarian cancer,etc.)and other diseases.Our previous studies have identified a novel SERM with three-dimensional topological structure-oxabicycloheptene sulfonate(OBHS)for ER?,which is effective in vivo for the prevention and treatment of estrogen-dependent endometriosis and exhibits neuroprotection against ?-amyloid(A?)-induced neurotoxicity.Here,using Ch IP-seq and RNA-seq analysis,we found that OBHS rapidly induced genome-wide ER? occupancy and behaves as a partial agonist and antagonist in ER? 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 ER?.Furthermore,we found that OBHS treatment resulted in defects of RNA polymerase II loading at the estrogenresponsive HRR genes,providing a mechanism for the regulation of HRR genes by OBHS.In summary,our studies not only reveal a novel SERM OBHS which uniquely targets the homologous recombination and repair programs through ER? antagonism,but also propose a synthetic lethal strategy by combining OBHS with PARP inhibitor olaparib or genotoxic doxorubicin for ER?-responsive cancers.