Induction of multidrug resistance transporter ABCG2 by prolactin in human breast cancer cells

• Published in: Molecular pharmacology Vol. 83; no. 2; pp. 377 - 388
• Main Authors: Wu, Alex Man Lai, Dalvi, Pooja, Lu, Xiaoli, Yang, Mingdong, Riddick, David S, Matthews, Jason, Clevenger, Charles V, Ross, Douglas D, Harper, Patricia A, Ito, Shinya
• Format: Journal Article
• Language: English
• Published: United States 01.02.2013
• Subjects: ATP Binding Cassette Transporter, Sub-Family G, Member 2; ATP-Binding Cassette Transporters - biosynthesis; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Carcinoma, Ductal, Breast - genetics; Carcinoma, Ductal, Breast - metabolism; Cell Line, Tumor; Drug Resistance, Multiple; Female; Humans; Interferon-gamma - genetics; Interferon-gamma - metabolism; Janus Kinase 2 - genetics; Janus Kinase 2 - metabolism; MCF-7 Cells; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - genetics; Mitogen-Activated Protein Kinases - metabolism; Mutation - genetics; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Prolactin - pharmacology; Promoter Regions, Genetic - drug effects; RNA, Messenger - genetics; Signal Transduction - drug effects; Signal Transduction - genetics; STAT5 Transcription Factor - genetics; STAT5 Transcription Factor - metabolism; Transcription, Genetic - drug effects; Transcriptional Activation - drug effects
• ISSN: 0026-895X; 1521-0111
• DOI: 10.1124/mol.112.082362

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.