Estrogen receptor alpha mediates epithelial to mesenchymal transition, expression of specific matrix effectors and functional properties of breast cancer cells
2015 (English)In: Matrix Biology, ISSN 0945-053X, E-ISSN 1569-1802, Vol. 43, 42-60 p.Article in journal (Refereed) Published
The 17 beta-estradiol (E2)/estrogen receptor alpha (ER alpha) signaling pathway is one of the most important pathways in hormone-dependent breast cancer. E2 plays pivotal roles in cancer cell growth, survival, and architecture as well as in gene expression regulatory mechanisms. In this study, we established stably transfected MCF-7 cells by knocking down the ER alpha gene (designated as MCF-7/SP10 + cells), using specific shRNA lentiviral particles, and compared them with the control cells (MCF-7/c). Interestingly, ERa silencing in MCF-7 cells strongly induced cellular phenotypic changes accompanied by significant changes in gene and protein expression of several markers typical of epithelial to mesenchymal transition (EMT). Notably, these cells exhibited enhanced cell proliferation, migration and invasion. Moreover, ERa suppression strongly affected the gene and protein expression of EGFR and HER2 receptor tyrosine kinases, and various extracellular matrix (ECM) effectors, including matrix metalloproteinases and their endogenous inhibitors (MMPs/TIMPs) and components of the plasminogen activation system. The action caused by E2 in MCF-7/c cells in the expression of HER2, MT1-MMP, MMP1, MMP9, uPA, tPA, and PAI-1 was abolished in MCF-7/SP10 + cells lacking ERa. These data suggested a regulatory role for the E2/ER alpha pathway in respect to the composition and activity of the extracellular proteolytic molecular network. Notably, loss of ER alpha promoted breast cancer cell migration and invasion by inducing changes in the expression levels of certain matrix macromolecules (especially uPA, tPA, PAI-1) through the EGFR-ERK signaling pathway. In conclusion, loss of ERa in breast cancer cells results in a potent EMT characterized by striking changes in the expression profile of specific matrix macromolecules highlighting the potential nodal role of matrix effectors in breast cancer endocrine resistance.
Place, publisher, year, edition, pages
2015. Vol. 43, 42-60 p.
Breast cancer, Estrogen receptor, EGFR, Epithelial to mesenchymal transition, Matrix metalloproteinases, uPA, tPA, Invasion, Migration
Biochemistry and Molecular Biology
IdentifiersURN: urn:nbn:se:uu:diva-258549DOI: 10.1016/j.matbio.2015.02.008ISI: 000356557300005PubMedID: 25728938OAI: oai:DiVA.org:uu-258549DiVA: diva2:841947
FunderEuropean Science Foundation (ESF)