Estrogen Receptor Beta 1: A Potential Therapeutic Target for Female Triple Negative Breast Cancer

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the absence of estrogen receptor alpha, progesterone receptor, and HER2. These receptors often serve as targets in breast cancer treatment. As a result, TNBCs are difficult to treat and have a high propensity to metastasize to distant organs. For these reasons, TNBCs are responsible for over 50% of all breast cancer mortalities while only accounting for 15% to 20% of breast cancer cases. However, estrogen receptor beta 1 (ER beta 1), an isoform of the ESR2 gene, has emerged as a potential therapeutic target in the treatment of TNBCs. Using an in vivo xenograft preclinical mouse model with human TNBC, we found that expression of ER beta 1 significantly reduced both primary tumor growth and metastasis. Moreover, TNBCs with elevated levels of ER beta 1 showed reduction in epithelial to mesenchymal transition markers and breast cancer stem cell markers, and increases in the expression of genes associated with inhibition of cancer cell invasiveness and metastasis, suggesting possible mechanisms underlying the antitumor activity of ER beta 1. Gene expression analysis by quantitative polymerase chain reaction and RNA-seq revealed that treatment with chloroindazole, an ER beta-selective agonist ligand, often enhanced the suppressive activity of ER beta 1 in TNBCs in vivo or in TNBC cells in culture, suggesting the potential utility of ER beta 1 and ER beta ligand in improving TNBC treatment. The findings enable understanding of the mechanisms by which ER beta 1 impedes TNBC growth, invasiveness, and metastasis and consideration of ways by which treatments involving ER beta might improve TNBC patient outcome.