title: Transcription factor Ets1 cooperates with estrogen receptor α to stimulate estradiol-dependent growth in breast cancer cells and tumors.
abstract: The purpose of this study was to explore the role of transcription factor Ets1 in estrogen receptor α (ERα)-positive breast cancer progression. We expressed human Ets1 or empty vector in four human ERα-positive breast cancer cell lines and observed increased colony formation. Further examination of cellular responses in stable Ets1-expressing MCF7 clones displayed increased proliferation, migration, and invasion. Ets1-expressing MCF7 tumors grown in the mammary fat pads of nude mice exhibited increased rates of tumor growth (7.36±2.47 mm(3)/day) compared to control MCF7 tumors (2.52±1.70 mm(3)/day), but maintained their dependence on estradiol for tumor growth. Proliferation marker Ki-67 staining was not different between control and Ets1-expressing tumors, but Ets1-expressing tumors exhibited large necrotic centers and elevated apoptotic staining. Ets1 was shown to cooperate with ERα and the p160 nuclear receptor coactivator (NCOA/SRC) family to increase activation of a consensus estrogen response element luciferase reporter construct. Ets1-expressing MCF7 cells also exhibited elevated expression of the ERα target genes, progesterone receptor and trefoil factor 1. Using GST-pulldown assays, Ets1 formed stable complexes containing both ERα and p160 nuclear receptor coactivators. Taken together, these data suggest that the Ets1-dependent estradiol sensitization of breast cancer cells and tumors may be partially due to the ability of Ets1 to cooperate with ERα and nuclear receptor coactivators to stimulate transcriptional activity of estrogen-dependent genes.
authors.affiliation: Flint Animal Cancer Center, Department of Clinical Sciences, Colorado State University, Fort Collins, Colorado, United States of America.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Kalet
authors.forename: Sara R
authors.initials: SR
authors.lastname: Anglin
authors.forename: Anne
authors.initials: A
authors.lastname: Handschy
authors.forename: Liza E
authors.initials: LE
authors.lastname: O'Donoghue
authors.forename: Charles
authors.initials: C
authors.lastname: Halsey
authors.forename: Laura
authors.initials: L
authors.lastname: Chubb
authors.forename: Christopher
authors.initials: C
authors.lastname: Korch
authors.forename: Dawn L
authors.initials: DL
authors.lastname: Duval
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D004958:Estradiol / Q000378:metabolism* / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D061986:MCF-7 Cells; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011485:Protein Binding; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D047368:Tumor Burden / Q000187:drug effects; D014410:Tumor Stem Cell Assay
chemical_list: D047628:Estrogen Receptor alpha; D019394:Ki-67 Antigen; D046912:Multiprotein Complexes; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D050784:Proto-Oncogene Protein c-ets-1; D004958:Estradiol