Survivin upregulation, dependent on leptin-EGFR-Notch1 axis, is essential for leptin-induced migration of breast carcinoma cells

• Type of Material: Article
• Authors: Brandi B. Knight, Emory University; Gabriela M Oprea, Emory University; Arumugam Nagalingam, Emory University; Lily Yang, Emory University; Cynthia Cohen, Emory University; Neeraj K. Saxena, University of Maryland; Dipali Sharma, Johns Hopkins University
• Language: English
• Date: 2011-08-01
• Publisher: BioScientifica
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2011 Society for Endocrinology.
• Final Published Version (URL): http://dx.doi.org/10.1530/ERC-11-0075
• Title of Journal or Parent Work: Endocrine-Related Cancer
• ISSN: 1351-0088
• Volume: 18
• Issue: 4
• Start Page: 413
• End Page: 428
• Grant/Funding Information: This work was supported by grants NIDDK NIH (K01DK076742 and R03DK089130 to NKS), NCI NIH (R01CA131294 to DS), CDMRP BCRP (BC030963 to DS), The Susan G. Komen for the Cure (BCTR0503526 to DS), and Mary K Ash Foundation (DS).
• Keywords: ACTIVATION; CANCER-CELLS; SIGNALING PROMOTES; MAMMARY-TUMORS; DOWN-REGULATION; Endocrinology & Metabolism; Life Sciences & Biomedicine; Science & Technology; EXPRESSION; GROWTH-FACTOR RECEPTOR; INHIBITOR-INDUCED APOPTOSIS; COLORECTAL-CANCER; Oncology; WILD-TYPE P53
• Research Categories: Health Sciences, Oncology; Health Sciences, Pathology; Health Sciences, Medicine and Surgery

Abstract

Obese breast cancer patients exhibit a higher risk for larger tumor burden and an increased likelyhood of metastasis. The molecular effects of obesity on carcinogenesis are mediated by the autocrine and paracrine effects of the adipocytokine leptin. Leptin participates in the tumor progression and metastasis of human breast. We show that leptin induces clonogenicity and increases the migration potential of breast cancer cells. We found that survivin expression is induced in response to leptin. In this study, we examine the role and leptin-mediated regulation of survivin. Leptin treatment leads to survivin upregulation, due in part to the activation ofNotch1 and the release of a transcriptionally active Notch1 intracellular domain (NICD). Chromatin immunoprecipitation analysis shows that NICD gets recruited to the survivin promoter at the CSL (CBF1/RBP-Jk, Su(H), Lag-1) binding site in response to leptin treatment. Inhibition of Notch1 activity inhibits leptin-induced survivin upregulation. Leptin-induced transactivation of epidermal growth factor receptor (EGFR) is involved in leptin-mediated Notch1 and survivin upregulation, demonstrating a novel upstream role of leptin-EGFR-Notch1 axis. We further show that leptin-induced migration of breast cancer cells requires survivin, as overexpression of survivin further increases, whereas silencing survivin abrogates leptin-induced migration. Using a pharmacological approach to inhibit survivin, we show that 3-hydroxy-3-methylglutaryl-coenzyme-A-reductase inhibitors, such as lovastatin, can effectively inhibit leptin-induced survivin expression and migration. Importantly, leptin increased breast tumor growth in nude mice. These data show a novel role for survivin in leptin-induced migration and put forth pharmacological survivin inhibition as a potential novel therapeutic strategy. This conclusion is supported by in vivo data showing the overexpression of leptin and survivin in epithelial cells of high-grade ductal carcinomas in situ and in high-grade invasive carcinomas.