title: Estrogen-induced aurora kinase-A (AURKA) gene expression is activated by GATA-3 in estrogen receptor-positive breast cancer cells.
abstract: Aurora-A is a proto-oncogenic mitotic kinase that is frequently overexpressed in human epithelial malignancies including in breast and ovarian cancers. The mechanism of transcriptional upregulation of Aurora-A in human breast cancer is not yet elucidated. We report herein that Aurora-A transcription is positively regulated by GATA-3 in response to estrogen in estrogen receptor α (ERα)-positive cells. Transient expression of aurora-A promoter deletion mutants in luciferase constructs identified a GATA binding sequence motif as a functional regulatory element in ERα-positive breast cancer cells. Electrophoretic mobility shift assay identified the binding of regulatory proteins to the GATA element. Anti-GATA-3 antibody generated a supershifted complex. Recruitment of GATA-3 to the aurora-A promoter was verified by chromatin immunoprecipitation analysis with GATA-3 antibody. Ectopic expression of GATA-3 resulted in elevated expression of Aurora-A in both ERα-positive and negative cells while siRNA-mediated silencing led to downregulation of endogenous Aurora-A in ERα-positive cells. Estrogen treatment of ERα-positive cells induced increased Aurora-A expression with enhanced recruitment of GATA-3 to the aurora-A promoter. Finally, in the ACI rat model of estrogen-induced breast cancer, known to be associated with elevated Aurora-A expression, we observed increased expression of GATA-3 in preinvasive and invasive mammary epithelial cells exposed to prolonged estrogen treatment and in developing breast tumors. These results demonstrate a direct positive role of estrogen in regulating Aurora-A expression through activation of the ERα-GATA-3 signaling cascade and suggest that this pathway may be critical in the origin of estrogen-stimulated sporadic breast cancer.
authors.affiliation: Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
authors.forename: Shoulei
authors.initials: S
authors.lastname: Jiang
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Katayama
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.forename: Sara Antonia
authors.initials: SA
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Hong
authors.forename: Laszlo
authors.initials: L
authors.lastname: Radvanyi
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Li
authors.forename: Subrata
authors.initials: S
authors.lastname: Sen
mesh_terms: D000818:Animals; D064096:Aurora Kinase A; D064127:Aurora Kinases; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D011960:Receptors, Estrogen; C576917:AURKA protein, human; C576920:Aurka protein, rat; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases