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This Article Accepted manuscript (PDF) All Versions of this Article: JOE-08-0215v1 199/2/221    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Perera, C. Articles by Camarillo, I. Search for Related Content PubMed PubMed Citation Articles by Perera, C. Articles by Camarillo, I.

C Perera, Department of Biological Sciences, Purdue University, West lafayette, United States
H Chin, Department of Biological Sciences, Purdue University, West Lafayette, United States
N Duru, Department of Biological Sciences, Purdue University, West Lafayette, United States
I Camarillo, Department of Biological Sciences, Purdue Cancer Center, Purdue University, West Lafayette, United States

Correspondence: Candida Perera, Email: candidanp{at}yahoo.com

Abstract

Obesity is a recently established risk factor for breast cancer incidence and mortality. A characteristic of obesity is elevated circulating levels of adipocyte-derived hormone leptin. Evidence indicates leptin plays an important role in mammary tumor formation, however the mechanisms involved are poorly understood. Towards better defining the role of leptin in breast cancer, herein we describe the identification of leptin-regulated genes in hormone responsive MCF-7 human breast cancer cells using a microarray system. More than 64 leptin-regulated genes were identified including those for growth factors, cell cycle regulators, extracellular matrix proteins and genes associated with metastasis. Cell cycle genes up-regulated by leptin include cyclins D and G, CDK2, p21, p27 and p16. Leptin suppressed the expression of TGF-beta, a cell cycle suppressor. Determining the significance of this effect, treatment of MCF-7 cells with TGF-beta abrogated leptin-stimulated proliferation. Leptin up-regulated the expression of CTGF, villin 2 and basigin, factors that are associated with extracellular matrix and are known to impact tumor growth. Finally, leptin induced the expression of anti-apoptotic genes BCL2 and survivin and reduced the expression of apoptotic genes. The effect of leptin on MCF-7 survival was evaluated via TUNNEL assay and demonstrated a 6-fold reduction of apoptosis in leptin treated cells, compared to controls. These data suggest leptin promotes mammary tumor growth through multiple mechanisms including regulating the cell cycle, apoptosis, and by modulating the extracellular environment. The identification of leptin-regulated genes begins to provide mechanistic links into the relationship between obesity and breast cancer incidence and morbidity.