Inhibition of TNBC Progression by ERβ

Parama Dey, Alexander Wang, Yvonne Ziegler, Sandeep Kumar, Shunchao Yan, Sung Hoon Kim, John A Katzenellenbogen, Benita S Katzenellenbogen
Endocrinology, Volume 163, Issue 12, December 2022, bqac172
https://doi.org/10.1210/endocr/bqac172

Abstract

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 (ERβ1), 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 ERβ1 significantly reduced both primary tumor growth and metastasis. Moreover, TNBCs with elevated levels of ERβ1 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 ERβ1. Gene expression analysis by quantitative polymerase chain reaction and RNA-seq revealed that treatment with chloroindazole, an ERβ-selective agonist ligand, often enhanced the suppressive activity of ERβ1 in TNBCs in vivo or in TNBC cells in culture, suggesting the potential utility of ERβ1 and ERβ ligand in improving TNBC treatment. The findings enable understanding of the mechanisms by which ERβ1 impedes TNBC growth, invasiveness, and metastasis and consideration of ways by which treatments involving ERβ might improve TNBC patient outcome.

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