Mechanisms of leptin in mammary tumorigenesis

Candida Perera, Purdue University

Abstract

Obesity is a recently established risk factor for breast cancer incidence and mortality. A characteristic of obesity is elevated circulating levels of the adipocyte-derived hormone leptin. Evidence indicates leptin plays an important role in mammary tumorigenesis, however, the mechanisms involved have not been delineated. To better understand the role of leptin in tumor growth, leptin regulated genes and secreted proteins were identified in MCF-7 human breast cancer cells using microarray and proteomic approaches. Leptin significantly increased proliferation and protein secretion in MCF-7 cells. Abundant proteins secreted by MCF-7 cells were identified by 2D gel electrophoresis coupled with MALDI-TOF mass spectrometry. These included KF10 Collagen Precursor, an extracellular matrix protein, Serologically Defined Breast Cancer Antigen NY-BR-62 and Coractin Isoform A, a mammary carcinoma associated protein. Low abundant secreted proteins regulated by leptin were identified using cytokine antibody arrays. In leptin treated cells the levels of MCSF, TNF-β and FGF-9 were all increased in the media. Conversely, leptin treatment decreased the levels of IGFBP-3 and TGF-β3 in the media. All these growth factors have been shown to be associated with cancer cell proliferation. Supporting proteomic data, microarray analysis identified over 50 leptin-regulated genes in MCF-7 cells including genes for growth factors, cell cycle regulators and extracellular matrix proteins. Together, proteomic and genomic data indicate leptin alters extracellular components including collagen, a protein important for tumor cell growth and migration. Subsequent studies focusing on collagen demonstrated that leptin increased the mRNA and protein levels of collagens I, III and N in MCF-7 cells in an ERK-kinase and P13-kinase dependent manner. The influence of leptin on collagen was also observed in vivo, where mammary tumors from obese rats contained higher levels of collagen. Together, these data suggest that, leptin regulates mammary tumor cell behavior through multiple mechanisms. In addition to activating mitogenic cell signaling pathways, leptin regulates mammary tumor cell growth by regulating autocrine or paracrine factors and modulating the extracellular environment. Identification of leptin-regulated factors provides mechanistic links into the relationship between obesity and increased breast cancer incidence and morbidity.

Degree

Ph.D.

Advisors

Camarillo, Purdue University.

Subject Area

Bioinformatics|Oncology

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