Functional And Mechanistic Studies Of Anti-breast Cancer Effects Of A Novel Multi-target Selective Estrogen Receptor Degrader Obhsa Derivative

Breast cancer(BC)has become the leading cancer type and disease burden for female population around the world.Over 2.3 million female breast cancer new cases were reported in 2020,which represented 11.7%of all cancer cases.Breast cancer subtypes can be defined based on the expression of estrogen receptor(ER),progesterone receptors(PR)and human epidermal growth factor 2(HER2).Approximately 70%of breast cancers are estrogen receptor positive(ER~+)and depend on estrogen receptor(ER)signaling for their progression.ERs belong to a superfamily of nuclear receptors and can serve as ligand-dependent transcriptional factors.Usually,ERs are activated due to binding of steroid estrogen hormones and then translocate from cell cytosol to nucleus.After recruiting a set of co-activators to its target gene regulation regions,such as promoter,ERs are able to regulate the transcription of target genes.ERs exist in two major forms,one of which is ERα.The role of ERαencoded by the ESR1 gene,in promoting breast cancer growth and proliferation has been reported by a lot of research.ER inhibitors are regarded as a standard of care for ERαpositive breast cancer.Selective Estrogen Receptor Modulators(SERMs)are ER ligands that act like estrogens in some tissues,but block estrogen signaling in others.And some of SERMs have been reported as ER inhibitors in breast cancer,such as tamoxifen,which has been widely used in hormonal therapy to address breast cancer.However,not all breast cancer responds to approved SERMs therapy,and some of cancer cells could develop resistance despite primary therapy benefits.Therefore,there is urgently requirement for developing new molecular actors involved in endocrine therapy.Autophagy is a highly conserved process that could serve as a cytoprotective mechanism,allowing them to survive stressful environments such as nutrient deficiencies and hypoxia environments.This dynamic process supports cellular homeostasis by transporting and degrading misfold proteins or damaged organelles in lysosome and then recycling materials.lysosomes are essential for maturation,fusion and degradation of autophagy.Previous studies demonstrate that the disturbance of autophagy balance can serve as a critical role to accelerate cancel cell death.Here,we prove that ERαis generally highly expressed in breast cancer tissue,and due to the high protein level of ERα,MCF-7,T47D,and LCC2 cell lines are favorable models for the study of ERαfunction.It is proved that ERαhas significant clinical value and is an important molecular target for breast cancer treatment.Patients with high ERαexpression have a better overall survival rate due to access to endocrine therapy.Moreover,7-oxabicyclo[2.2.1]heptene sulfonamide(OBHSA),a novel bicyclic core compound,showed anti-tumor effects on cancer cells.The presence of compound 17e,a novel selective estrogen receptor degrader,results in the impairment of breast cancer cells both in vitro and in vivo by inducing ERαdegradation and promoting autophagy-lysosome pathway,which may contribute to cell cycle arrest in the G1/S phase via decreasing MYC level.In the present study,we investigated the biological effects of compound 17e on breast cancer and provide some molecular and cellular mechanism details about the anti-cancer effects of compound 17e in the hope of accelerating the pace of development of potential SERDs which may benefit BC patients in the future.