title: Hypothalamic gene transfer of BDNF inhibits breast cancer progression and metastasis in middle age obese mice.
abstract: 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.
authors.affiliation: 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.
authors.forename: Xianglan
authors.initials: X
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Travis
authors.initials: T
authors.lastname: McMurphy
authors.affiliation: 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.
authors.forename: Run
authors.initials: R
authors.lastname: Xiao
authors.affiliation: 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.
authors.forename: Andrew
authors.initials: A
authors.lastname: Slater
authors.affiliation: 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: 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.
authors.forename: Lei
authors.initials: L
authors.lastname: Cao
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000502:physiology*; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D005260:Female; D007031:Hypothalamus / Q000378:metabolism*; D051379:Mice; D008820:Mice, Obese
chemical_list: D019208:Brain-Derived Neurotrophic Factor