Crosstalk between 17β-Estradiol and TGF-β Signaling Modulates Glioblastoma Progression

Epithelial-mesenchymal transition (EMT) is an essential mechanism contributing to glioblastoma multiforme (GBM) progression, the most common and malignant brain tumor. EMT is induced by signaling pathways that crosstalk and regulate an intricate regulatory network of transcription factors. It has been shown that downstream components of 17 beta-estradiol (E2) and transforming growth factor beta (TGF-beta) signaling pathways crosstalk in estrogen-sensitive tumors. However, little is known about the interaction between the E2 and TGF-beta signaling components in brain tumors. We have investigated the relationship between E2 and TGF-beta signaling pathways and their effects on EMT induction in human GBM-derived cells. Here, we showed that E2 and TGF-beta negatively regulated the expression of estrogen receptor alpha (ER-alpha) and Smad2/3. TGF-beta induced Smad2 phosphorylation and its subsequent nuclear translocation, which E2 inhibited. Both TGF-beta and E2 induced cellular processes related to EMT, such as morphological changes, actin filament reorganization, and mesenchymal markers (N-cadherin and vimentin) expression. Interestingly, we found that the co-treatment of E2 and TGF-beta blocked EMT activation. Our results suggest that E2 and TGF-beta signaling pathways interact through ER-alpha and Smad2/3 mediators in cells derived from human GBM and inhibit EMT activation induced by both factors alone.