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Induction of Multidrug Resistance Transporter ABCG2 by Prolactin in Human Breast Cancer Cells.
MedLine Citation:
PMID:  23150485     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
The multidrug transporter, breast cancer resistance protein (BCRP, ABCG2), is upregulated in certain chemoresistant cancer cells and in the mammary gland during lactation. We investigated the role of the lactogenic hormone prolactin in the regulation of ABCG2. Prolactin dose-dependently induced ABCG2 in T-47D human breast cancer cells. This induction was significantly reduced by short interfering RNA (siRNA)-mediated knockdown of Janus Kinase 2 (JAK2). Knockdown or pharmacological inhibition of the down-stream signal transducer and activator of transcription-5 (STAT5) also blunted the induction of ABCG2 by prolactin, suggesting a role for the JAK2/STAT5 pathway in prolactin-induced ABCG2 expression. Corroborating these findings, we observed prolactin-stimulated STAT5 recruitment to a region containing a putative GAS element at -434bp upstream of the ABCG2 transcription start site. Introduction of a single mutation to the -434 GAS element significantly attenuated prolactin-stimulated activity of a luciferase reporter driven by the ABCG2 gene promoter and 5'-flanking region containing the -434 GAS motif. In addition, this GAS element showed strong copy number dependency in its response to prolactin treatment. Interestingly, inhibitors against the mitogen-activated protein kinase (MAPK) and phosphoinositide-3-kinase (PI3K) signalling pathways significantly decreased the induction of ABCG2 by prolactin without altering STAT5 recruitment to the GAS element. We conclude that the JAK2/STAT5 pathway is required but not sufficient for the induction of ABCG2 by prolactin.
Authors:
Alex Man Lai Wu; Pooja Dalvi; Xiaoli Lu; Mingdong Yang; David S Riddick; Jason Matthews; Charles V Clevenger; Douglas D Ross; Patricia A Harper; Shinya Ito
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-11-13
Journal Detail:
Title:  Molecular pharmacology     Volume:  -     ISSN:  1521-0111     ISO Abbreviation:  Mol. Pharmacol.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-14     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0035623     Medline TA:  Mol Pharmacol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
1 Hospital for Sick Children;
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