ERα Regulates The Role And Mechanism Of HDAC3 In Endocrine Resistant Breast Cancer Cells

Breast cancer is a serious threat to women’s health all over the world.About 70% of breast cancer patients are ERα positive,and the most commonly used treatment for these patients is endocrine therapy.Tamoxifen is the first-line drug for endocrine therapy.After treatment with tamoxifen,the recurrence rate of patients decreases by approximately 40%,and the mortality rate decreases by approximately 30%.However,patients were treated with tamoxifen for 5 years,and still one-third of patients relapsed within 15 years.Due to the emergence of endocrine resistance,the cure rate of breast cancer patients is limited.Therefore,reversing the drug resistance of endocrine therapy plays an extremely important role in the treatment of ERα positive breast cancer.Downregulation of ERα expression is one of the main mechanisms of endocrine resistance.Recent studies have shown that HDAC3 is highly expressed in ERα-negative breast cancer cells.HDAC inhibitors may also effectively overcome the resistance of breast cancer patients to tamoxifen.Here,our goal is to unravel the molecular mechanisms of ERα and HDAC3 in promoting the proliferation advantages of endocrine-resistant breast cancer cells.In this paper,the expression levels of ERα and HDAC3 were detected by RTq PCR and Western blot experiments.We found that the expression of ERα in tamoxifen-resistant(T47D-TAR)cells was reduced,while the expression level of HDAC3 protein was up-regulated.Through further research,we found that downregulation of ERα expression in breast cancer cells reduces the cleavage of HDAC3 protein by reducing the expression of caspase7,and ultimately improves the stability of HDAC3 protein.Changes in histone acetylation levels affect gene transcription.Our study determined that ERα positively regulates H3K9 ac and H4K16 ac expression,while HDAC3 negatively regulates H3K9 ac and H4K16 ac expression.Our study found that inhibiting HDAC3 expression in T47D-TAR cells upregulates CDKN1 A expression.Finally,we confirmed by cloning experiments that inhibiting the expression of HDAC3 can significantly reduce the proliferation of T47D-TAR cells.Therefore,we conclude that endocrine-resistant breast cancer cells with downregulated ERα expression retain their proliferative advantages by up-regulating HDAC3 protein expression,and HDAC3 can be used as an effective treatment target for endocrine-resistant breast cancer.