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The multifactorial role of leptin in driving the breast cancer microenvironment

Nature Reviews Endocrinology volume 8, pages 263–275 (2012)Cite this article

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Abstract

Adipose-tissue-derived signaling molecules, including the adipokines, are emerging as key candidate molecules that link obesity with cancer. Peritumoral, stromal, adipose tissue and secreted adipokines, particularly leptin, have important roles in breast cancer biology. For example, leptin signaling contributes to the metabolic features associated with breast cancer malignancy, such as switching the cells' energy balance from mitochondrial β-oxidation to the aerobic glycolytic pathway. Leptin also shapes the tumor microenvironment, mainly through its ability to potentiate both migration of endothelial cells and angiogenesis, and to sustain the recruitment of macrophages and monocytes, which in turn secrete vascular endothelial growth factor and proinflammatory cytokines. This article presents an overview of current knowledge on the involvement of leptin in the pathogenesis and progression of breast cancer, highlighted by human, in vitro and animal studies. Data are presented on the functional crosstalk between leptin and estrogen signaling, which further contributes to promotion of breast carcinogenesis. Finally, future perspectives and clinical applications in which leptin and the leptin receptor are considered as potential therapeutic targets for breast cancer are reviewed.

Key Points

  • Breast tumor development and progression is a long-term and continuous process that relies on reciprocal interactions between the tumor cell and its surrounding microenvironment

  • Leptin is one of the adipokines secreted by adipocytes—the most abundant cell type surrounding breast cancer cells—and is linked to breast cancer development

  • Breast cancer cells also produce leptin, which acts in an autocrine and paracrine manner to promote angiogenesis, tumor cell proliferation, migration and invasion, and has proinflammatory effects

  • Local estrogen production is increased by leptin, which amplifies estrogen signaling, further contributing to breast tumorigenesis

  • Leptin and leptin-receptor signaling might represent a potential therapeutic target for breast cancer treatment—particularly in women with obesity

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Figure 1: Leptin signaling.
Figure 2: Leptin-induced endothelial cell migration and angiogenesis.
Figure 3: Leptin-mediated activation of macrophages.
Figure 4: Proposed model of leptin-mediated modulation of cadherin-1 expression in breast cancer.
Figure 5: Crosstalk between leptin and estrogen signaling in human breast tissue.
Figure 6: Proposed model of PPARγ-mediated regulation of leptin expression and function in breast cancer cells.

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Acknowledgements

S. Andò's and S. Catalano's research work is supported by Associazione Italiana per la Ricerca sul Cancro (AIRC) grant I G 1482.

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  1. Department of Cell Biology and Centro Sanitario, University of Calabria, via Pietro Bucci, Arcavacata di Rende, 87036, Italy

    Sebastiano Andò

  2. Department of Pharmaco-Biology and Centro Sanitario, University of Calabria, via Pietro Bucci, Arcavacata di Rende, 87036, Italy

    Stefania Catalano

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  1. Sebastiano Andò
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The authors contributed equally to all aspects of the manuscript, including researching data for the article, writing and discussions of the content, as well as review and/or editing of the article before submission.

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Andò, S., Catalano, S. The multifactorial role of leptin in driving the breast cancer microenvironment. Nat Rev Endocrinol 8, 263–275 (2012). https://doi.org/10.1038/nrendo.2011.184

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