Estrogen receptor beta modulates breast cancer cells functional properties, signaling and expression of matrix molecules

Estrogen receptors have pivotal roles in breast cancer growth and progression. ER alpha has been clearly shown to play key role in hormone-dependent breast cancer properties, but little is known for the isoform ER beta. To evaluate the role of ER beta, we established stably transfected ER beta-suppressed MDA-MB-231 breast cancer cells by knocking down the human ER beta gene, using specific shRNA lentiviral particles. As observed by scanning electron microscopy, the ER beta suppression induces significant phenotypic changes in these cells, as compared to the control cells. Notably, the down-regulation of ER beta decreases the expression of the mesenchymal markers fibronectin and vimentin, whereas it increases the expression levels of the epithelial marker E-cadherin and cell junctions. These alterations are followed by reduced levels of the functional cell properties that promote the aggressiveness of these cells, such as proliferation, migration, spreading capacity, invasion and adhesion on collagen I. Notably, the down-regulation of ER beta reduces the migration of breast cancer cells through the tyrosine kinase receptors EGFR/IGF-IR and the JAK/STAT signaling pathways. Moreover, ER beta has a crucial role on the gene expression of several matrix mediators, including the proteoglycans syndecans-2/-4 and serglycin, several matrix metalloproteinases, plasminogen activation system components and receptor tyrosine kinases. These data clearly show that ER beta plays a crucial role in the cell behavior and ECM composition of the highly aggressive MDA-MB-231 cells and opens a new area of research to further understand its role and to improve pharmaceutical targeting of the non-hormone dependent breast cancer. (C) 2016 Elsevier B.V. All rights reserved.