Estrogen receptor β target gene expression reveals novel repressive functions in aggressive breast cancer

Inflammatory breast cancer (IBC) is a highly metastatic breast carcinoma, frequently characterized by estrogen receptor alpha (ERα) negativity and limited treatment options. Our previous research showed that the second ER subtype, ERβ, is associated with reduced metastasis in IBC patients and xenografts. We linked its anti-metastatic function to the inhibition of actin-based cell migration and Rho GTPase signaling. In this study, we employed a genomics approach to fully delineate the signaling underlying the anti-metastatic activity of ERβ. By cross-examining responsive mRNAs and miRNAs against chromatin binding sites in IBC cells with agonist-activated transfected and endogenous ERβ, we identified key regulatory binding motifs, direct targets, and associated biological functions. Our findings implicate pathways in development, metabolism and tumor microenvironment in the anti-metastatic action of ERβ. Clinical dataset analysis associates downstream factors with patient outcomes, indicating new molecules with therapeutic potential and highlighting the relevance of tumor repressive ERβ signaling in breast cancer.