Targeting the IKKβ/mTOR/VEGF signaling pathway as a potential therapeutic strategy for obesity-related breast cancer

Chun Te Chen, Yi Du, Hirohito Yamaguchi, Jung Mao Hsu, Hsu Ping Kuo, Gabriel N. Hortobagyi, Mien Chie Hung

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Clinical correlation studies have clearly shown that obesity is associated with breast cancer risk and patient survival. Although several potential mechanisms linking obesity and cancers have been proposed, the detailed molecular mechanism of obesity-mediated breast tumorigenesis has not yet been critically evaluated. In this study, we evaluated the effects of obesity on mammary tumor initiation and progression using mice with genetic and diet-induced obesity bearing mammary tumor xenografts and mouse mammary tumor virus-neu transgenic mice that were fed a high-fat diet. We show that obesity promoted mammary tumor growth and development in these animal models. Moreover, the expressions of TNFα, VEGF, IKKβ, and mTOR are upregulated in mammary tumors of obese mice, suggesting that the IKKβ/mTOR/VEGF signaling pathway is activated by TNFα in the tumors of obese mice. More importantly, inhibitors (rapamycin, bevacizumab, and aspirin) that target members of the pathway suppressed tumorigenesis and prolonged survival more effectively in obese mice than in nonobese mice. Here, we not only identified a specific signaling pathway that contributes to mammary tumorigenesis in obese mice but also a strategy for treating obesity-mediated breast cancer.

Original languageEnglish (US)
Pages (from-to)2212-2221
Number of pages10
JournalMolecular cancer therapeutics
Volume11
Issue number10
DOIs
StatePublished - Oct 2012
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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