title: Pubertal high fat diet: effects on mammary cancer development.
abstract: BACKGROUND
  Epidemiological studies linking dietary fat intake and obesity to breast cancer risk have produced inconsistent results. This may be due to the difficulty of dissociating fat intake from obesity, and/or the lack of defined periods of exposure in these studies. The pubertal mammary gland is highly sensitive to cancer-causing agents. We assessed how high fat diet (HFD) affects inflammation, proliferative, and developmental events in the pubertal gland, since dysregulation of these can promote mammary tumorigenesis. To test the effect of HFD initiated during puberty on tumorigenesis, we utilized BALB/c mice, for which HFD neither induces obesity nor metabolic syndrome, allowing dissociation of HFD effects from other conditions associated with HFD.
  
  
  METHODS
  Pubertal BALB/c mice were fed a low fat diet (12% kcal fat) or a HFD (60% kcal fat), and subjected to carcinogen 7,12-dimethylbenz[a]anthracene (DMBA)-induced tumorigenesis.
  
  
  RESULTS
  HFD elevated mammary gland expression of inflammatory and growth factor genes at 3 and 4 weeks of diet. Receptor activator of nuclear factor kappa-B ligand (RANKL), robustly induced at 4 weeks, has direct mitogenic activity in mammary epithelial cells and, as a potent inducer of NF-κB activity, may induce inflammatory genes. Three weeks of HFD induced a transient influx of eosinophils into the mammary gland, consistent with elevated inflammatory factors. At 10 weeks, prior to the appearance of palpable tumors, there were increased numbers of abnormal mammary epithelial lesions, enhanced cellular proliferation, increased growth factors, chemokines associated with immune-suppressive regulatory T cells, increased vascularization, and elevated M2 macrophages. HFD dramatically reduced tumor latency. Early developing tumors were more proliferative and were associated with increased levels of tumor-related growth factors, including increased plasma levels of HGF in tumor-bearing animals. Early HFD tumors also had increased vascularization, and more intra-tumor and stromal M2 macrophages.
  
  
  CONCLUSIONS
  Taken together in this non-obesogenic context, HFD promotion of inflammatory processes, as well as local and systemically increased growth factor expression, are likely responsible for the enhanced tumorigenesis. It is noteworthy that although DMBA mutagenesis is virtually random in its targeting of genes in tumorigenesis, the short latency tumors arising in animals on HFD showed a unique gene expression profile, highlighting the potent overarching influence of HFD.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhao
authors.forename: Ying Siow
authors.initials: YS
authors.lastname: Tan
authors.forename: Mark D
authors.initials: MD
authors.lastname: Aupperlee
authors.forename: Ingeborg M
authors.initials: IM
authors.lastname: Langohr
authors.forename: Erin L
authors.initials: EL
authors.lastname: Kirk
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Troester
authors.forename: Richard C
authors.initials: RC
authors.lastname: Schwartz
authors.forename: Sandra Z
authors.initials: SZ
authors.lastname: Haslam
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D059305:Diet, High-Fat; D005260:Female; D020869:Gene Expression Profiling; D006728:Hormones / Q000097:blood; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000209:etiology* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D051379:Mice; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D012741:Sexual Maturation; D015398:Signal Transduction; D013997:Time Factors; D059016:Tumor Microenvironment
chemical_list: D016207:Cytokines; D006728:Hormones; D018836:Inflammation Mediators; D036341:Intercellular Signaling Peptides and Proteins