title: Targeting the IKKβ/mTOR/VEGF signaling pathway as a potential therapeutic strategy for obesity-related breast cancer.
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.
authors: Department of Molecular and Cellular Oncology, Unit 0079, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
authors: Chun-Te
authors: CT
authors: Chen
authors: Yi
authors: Y
authors: Du
authors: Hirohito
authors: H
authors: Yamaguchi
authors: Jung-Mao
authors: JM
authors: Hsu
authors: Hsu-Ping
authors: HP
authors: Kuo
authors: Gabriel N
authors: GN
authors: Hortobagyi
authors: Mien-Chie
authors: MC
authors: Hung
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply / Q000209:etiology* / Q000473:pathology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000098:blood supply / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D009389:Neovascularization, Pathologic; D009765:Obesity / Q000150:complications* / Q000473:pathology; D015398:Signal Transduction; D016019:Survival Analysis; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D058570:TOR Serine-Threonine Kinases; D051550:I-kappa B Kinase