Induction of Multidrug Resistance Transporter ABCG2 by Prolactin in Human Breast Cancer Cells

• DOI: 10.1124/mol.112.082362
• Publication Date: 2012-11-14T02:08:57Z
• 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
• Keywords: Abcg2

The multidrug transporter, breast cancer resistance protein, ABCG2, is up-regulated in certain chemoresistant cells and the mammary gland during lactation. We investigated role of lactogenic hormone prolactin (PRL) regulation ABCG2. PRL dose-dependently induced ABCG2 expression T-47D human cells. This induction was significantly reduced by short-interfering RNA–mediated knockdown Janus kinase 2 (JAK2). Knockdown or pharmacologic inhibition down-stream signal transducer activator transcription-5 (STAT5) also blunted PRL, suggesting a for JAK2/STAT5 pathway PRL-induced expression. Corroborating these findings, we observed PRL-stimulated STAT5 recruitment to region containing putative γ-interferon activation sequence (GAS) element at −434 base pairs upstream transcription start site. Introduction single mutation GAS attenuated activity luciferase reporter driven gene promoter 5′-flanking motif. In addition, this showed strong copy number dependency its response treatment. Interestingly, inhibitors against mitogen-activated protein phosphoinositide-3-kinase signaling pathways decreased without altering element. conclude that required but not sufficient PRL.