Molecular cross-talk between ER and ID4 in breast cancer

NASIF DANIELA; ROQUÉ, MARÍA; BRANHAM MARIA T

Simposio; BUENOS AIRES BREAST CANCER SYMPOSIUM; 2021

Inhibitor of differentiation (ID) 4, a member of the ID family,has been shown to act as a tumor suppressor and asan oncogene in breast cancer. Our group has investigatedthis apparent discordant information and has found evidencethat ID4 acts as a tumor suppressor only in estrogen receptorER+ tumors and as an oncogene only in ER- tumors.Here we focus on ID4?s tumor suppressor role and furtherinvestigate why ID4 is aberrantly methylated exclusively inER+ tumors. EZH2 is a histone methyltransferase involvedin the tri-methylation of lysine 27 on histone 3 (H3K27me3)and also promotes DNA methylation via DNMT recruitment.In breast cancer EZH2 is overexpressed and downregulatesthe expression of tumor suppressor genes via increasedpromoter H3K27me3. Since ID4 is hyper-methylated inER+ tumors and since EZH2 expression is induced byestradiol we hypothesize that estradiol induces ID4 methylationthrough EZH2. We performed siRNA (EZH2), immunofluorescenceand chromatin immunoprecipitation (CHIP)experiments in MCF7 breast cancer cell lines. Our resultsshow that EZH2 regulates ID4 expression as confirmed bysiRNA experiments, that estrogen treatment increases EZH2expression and CHIP experiments reveal that estrogenadministration increases EZH2 and H3K27me3 marks onID4 promoter. Taken together our results show for the firsttime that estradiol induces ID4 methylation trough EZH2 inbreast cancer cell lines