Estrogen receptor alpha mediates epithelial to mesenchymal transition, expression of specific matrix effectors and functional properties of breast cancer cells.
The 17β-estradiol (E2)/estrogen receptor alpha (ERα) 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 ERα gene (designated as MCF-7/SP10+ cells), using specific shRNA lentiviral particles, and compared them with the control cells (MCF-7/c). Interestingly, ERα 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, ERα 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 ERα. These data suggested a regulatory role for the E2/ERα pathway in respect to the composition and activity of the extracellular proteolytic molecular network. Notably, loss of ERα 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 ERα 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.
Biochemistry, Biochemical Analysis & Matrix Pathobiology Res. Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras 26110, Greece.
Panagiotis
P
Bouris
Biochemistry, Biochemical Analysis & Matrix Pathobiology Res. Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras 26110, Greece.
Spyros S
SS
Skandalis
Biochemistry, Biochemical Analysis & Matrix Pathobiology Res. Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras 26110, Greece.
Zoi
Z
Piperigkou
Biochemistry, Biochemical Analysis & Matrix Pathobiology Res. Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras 26110, Greece.
Nikos
N
Afratis
Biochemistry, Biochemical Analysis & Matrix Pathobiology Res. Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras 26110, Greece; Université de Reims Champagne Ardenne, Laboratoire de Biochimie Médicale et de Biologie Moléculaire, Reims, France.
Konstantina
K
Karamanou
Biochemistry, Biochemical Analysis & Matrix Pathobiology Res. Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras 26110, Greece.
Alexios J
AJ
Aletras
Department of Medical Biochemistry and Microbiology, Ludwig Institute for Cancer Research, Science for Life Laboratory, Uppsala University, Box 582, SE 751 23 Uppsala, Sweden.
Aristidis
A
Moustakas
Biochemistry, Biochemical Analysis & Matrix Pathobiology Res. Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras 26110, Greece.
Achilleas D
AD
Theocharis
Biochemistry, Biochemical Analysis & Matrix Pathobiology Res. Group, Laboratory of Biochemistry, Department of Chemistry, University of Patras, Patras 26110, Greece. Electronic address: n.k.karamanos@upatras.gr.
Nikos K
NK
Karamanos
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D058750:Epithelial-Mesenchymal Transition; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D061986:MCF-7 Cells
C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha
Breast cancer; EGFR; Epithelial to mesenchymal transition; Estrogen receptor; Invasion; Matrix metalloproteinases; Migration; tPA; uPA