RT Journal Article
SR Electronic
T1 Induction of Multidrug Resistance Transporter ABCG2 by Prolactin in Human Breast Cancer Cells
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 377
OP 388
DO 10.1124/mol.112.082362
VO 83
IS 2
A1 Alex Man Lai Wu
A1 Pooja Dalvi
A1 Xiaoli Lu
A1 Mingdong Yang
A1 David S. Riddick
A1 Jason Matthews
A1 Charles V. Clevenger
A1 Douglas D. Ross
A1 Patricia A. Harper
A1 Shinya Ito
YR 2013
UL http://molpharm.aspetjournals.org/content/83/2/377.abstract
AB The multidrug transporter, breast cancer resistance protein, ABCG2, is up-regulated in certain chemoresistant cancer cells and in the mammary gland during lactation. We investigated the role of the lactogenic hormone prolactin (PRL) in the regulation of ABCG2. PRL dose-dependently induced ABCG2 expression in T-47D human breast cancer cells. This induction was significantly reduced by short-interfering RNA–mediated knockdown of Janus kinase 2 (JAK2). Knockdown or pharmacologic inhibition of the down-stream signal transducer and activator of transcription-5 (STAT5) also blunted the induction of ABCG2 by PRL, suggesting a role for the JAK2/STAT5 pathway in PRL-induced ABCG2 expression. Corroborating these findings, we observed PRL-stimulated STAT5 recruitment to a region containing a putative γ-interferon activation sequence (GAS) element at −434 base pairs upstream of the ABCG2 transcription start site. Introduction of a single mutation to the −434 GAS element significantly attenuated PRL-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 PRL treatment. Interestingly, inhibitors against the mitogen-activated protein kinase and phosphoinositide-3-kinase signaling pathways significantly decreased the induction of ABCG2 by PRL 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 PRL.