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Prolactin induces BCRP/ABCG2 expression in T‐47D breast cancer cells via activation of multiple signalling cascades
Author(s) -
Wu Alex,
Dalvi Pooja,
Yang Mingdong,
Lu Xiaoli,
Harper Patricia A,
Ito Shinya
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1047.2
Subject(s) - prolactin , abcg2 , gene knockdown , pi3k/akt/mtor pathway , ly294002 , stat5 , mapk/erk pathway , protein kinase b , downregulation and upregulation , gene silencing , endocrinology , chemistry , medicine , cancer research , biology , signal transduction , hormone , microbiology and biotechnology , transporter , cell culture , atp binding cassette transporter , biochemistry , genetics , gene
The drug transporter Breast Cancer Resistance Protein (BCRP/ABCG2) has been shown to be upregulated in certain drug resistant breast cancer cells and in the normal mammary gland during lactation. Given the important role of the lactogenic hormone prolactin in breast cancer and lactation biology, we investigated the effect of prolactin on BCRP expression in T‐47D human breast cancer epithelial cells. Prolactin upregulated BCRP mRNA and protein expression in a dose‐dependent manner. Induction of BCRP mRNA by prolactin was blocked by the transcription inhibitor actinomycin D. To characterize the mechanism responsible for prolactin‐induced BCRP mRNA expression, we systematically inhibited members of the three major pathways activated in prolactin signalling: JAK2/STAT5, MAPK, and PI3K/AKT. Knockdown of JAK2 by siRNA attenuated the prolactin‐BCRP response. Knockdown or pharmacological inhibition of STAT5 by siRNA or small molecule inhibitor, respectively, blunted prolactin‐induced BCRP mRNA expression. Treating cells in the presence of the MAPK pathway inhibitors PD98059 (20μM) and U0126 (10μM), and the PI3K pathway inhibitors LY294002 (10μM) and Wortmannin (25nM), significantly attenuated the effect of prolactin on BCRP mRNA expression. Taken together, our results demonstrate overlapping roles for JAK2/STAT5, MAPK, and PI3K/AKT signalling in prolactin‐induced BCRP expression. Funding provided by CIHR.