PMID- 24637454 OWN - NLM STAT- MEDLINE DCOM- 20150219 LR - 20211021 IS - 1525-0024 (Electronic) IS - 1525-0016 (Print) IS - 1525-0016 (Linking) VI - 22 IP - 7 DP - 2014 Jul TI - Hypothalamic gene transfer of BDNF inhibits breast cancer progression and metastasis in middle age obese mice. PG - 1275-1284 LID - S1525-0016(16)30719-5 [pii] LID - 10.1038/mt.2014.45 [doi] AB - Activation of the hypothalamus-adipocyte axis is associated with an antiobesity and anticancer phenotype in animal models of melanoma and colon cancer. Brain-derived neurotrophic factor (BDNF) is a key mediator in the hypothalamus leading to preferential sympathoneural activation of adipose tissue and the ensuing resistance to obesity and cancer. Here, we generated middle age obese mice by high fat diet feeding for a year and investigated the effects of hypothalamic gene transfer of BDNF on a hormone receptor-positive mammary tumor model. The recombinant adeno-associated viral vector-mediated overexpression of BDNF led to marked weight loss and decrease of adiposity without change of food intake. BDNF gene therapy improved glucose tolerance, alleviated steatosis, reduced leptin level, inhibited mouse breast cancer EO771 growth, and prevented the metastasis. The reduced tumor growth in BDNF-treated mice was associated with reduced angiogenesis, decreased proliferation, increased apoptosis, and reduced adipocyte recruitment and lipid accumulation. Moreover, BDNF gene therapy reduced inflammation markers in the hypothalamus, the mammary gland, the subcutaneous fat, and the mammary tumor. Our results suggest that manipulating a single gene in the brain may influence multiple mechanisms implicated in obesity-cancer association and provide a target for the prevention and treatment of both obesity and cancer. FAU - Liu, Xianglan AU - Liu X AD - Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio, USA; The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA. FAU - McMurphy, Travis AU - McMurphy T AD - Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio, USA; The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA. FAU - Xiao, Run AU - Xiao R AD - Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio, USA; The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA. FAU - Slater, Andrew AU - Slater A AD - Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio, USA; The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA. FAU - Huang, Wei AU - Huang W AD - Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio, USA; The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA. FAU - Cao, Lei AU - Cao L AD - Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio, USA; The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA. Electronic address: lei.cao@osumc.edu. LA - eng GR - R01 CA163640/CA/NCI NIH HHS/United States GR - CA178227/CA/NCI NIH HHS/United States GR - AG041250/AG/NIA NIH HHS/United States GR - R01 CA166590/CA/NCI NIH HHS/United States GR - R21 CA178227/CA/NCI NIH HHS/United States GR - R01 AG041250/AG/NIA NIH HHS/United States GR - CA166590/CA/NCI NIH HHS/United States GR - P30 CA016058/CA/NCI NIH HHS/United States GR - CA163640/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20140318 PL - United States TA - Mol Ther JT - Molecular therapy : the journal of the American Society of Gene Therapy JID - 100890581 RN - 0 (Brain-Derived Neurotrophic Factor) SB - IM MH - Animals MH - Brain-Derived Neurotrophic Factor/genetics/*physiology MH - Breast Neoplasms/genetics/pathology/*therapy MH - Female MH - Hypothalamus/*metabolism MH - Mice MH - Mice, Obese PMC - PMC4089014 EDAT- 2014/03/19 06:00 MHDA- 2015/02/20 06:00 PMCR- 2015/07/01 CRDT- 2014/03/19 06:00 PHST- 2013/12/07 00:00 [received] PHST- 2014/03/10 00:00 [accepted] PHST- 2014/03/19 06:00 [entrez] PHST- 2014/03/19 06:00 [pubmed] PHST- 2015/02/20 06:00 [medline] PHST- 2015/07/01 00:00 [pmc-release] AID - S1525-0016(16)30719-5 [pii] AID - 10.1038/mt.2014.45 [doi] PST - ppublish SO - Mol Ther. 2014 Jul;22(7):1275-1284. doi: 10.1038/mt.2014.45. Epub 2014 Mar 18.