title: Puberty-specific promotion of mammary tumorigenesis by a high animal fat diet.
abstract: BACKGROUND
  Increased animal fat consumption is associated with increased premenopausal breast cancer risk in normal weight, but not overweight, women. This agrees with our previous findings in obesity-resistant BALB/c mice, in which exposure to a high saturated animal fat diet (HFD) from peripuberty through adulthood promoted mammary tumorigenesis. Epidemiologic and animal studies support the importance of puberty as a life stage when diet and environmental exposures affect adult breast cancer risk. In this study, we identified the effects of peripubertal exposure to HFD and investigated its mechanism of enhancing tumorigenesis.
  
  
  METHODS
  Three-week-old BALB/c mice fed a low-fat diet (LFD) or HFD were subjected to 7,12-dimethylbenz[a]anthracene (DMBA)-induced carcinogenesis. At 9 weeks of age, half the mice on LFD were switched to HFD (LFD-HFD group) and half the mice on HFD were switched to LFD (HFD-LFD group). Tumor gene expression was evaluated in association with diet and tumor latency.
  
  
  RESULTS
  The peripubertal HFD reduced the latency of DMBA-induced mammary tumors and was associated with tumor characteristics similar to those in mice fed a continuous HFD. Notably, short-latency tumors in both groups shared gene expression characteristics and were more likely to have adenosquamous histology. Both HFD-LFD and continuous HFD tumors showed similar gene expression patterns and early latency. Adult switch from HFD to LFD did not reverse peripubertal HFD tumor promotion. Increased proliferation, hyperplasia, and macrophages were present in mammary glands before tumor development, implicating these as possible effectors of tumor promotion. Despite a significant interaction between pubertal diet and carcinogens in tumor promotion, peripubertal HFD by itself produced persistent macrophage recruitment to mammary glands.
  
  
  CONCLUSIONS
  In obesity-resistant mice, peripubertal HFD is sufficient to irreversibly promote carcinogen-induced tumorigenesis. Increased macrophage recruitment is likely a contributing factor. These results underscore the importance of early life exposures to increased adult cancer risk and are consistent with findings that an HFD in normal weight premenopausal women leads to increased breast cancer risk. Notably, short-latency tumors occurring after peripubertal HFD had characteristics similar to human basal-like breast cancers that predominantly develop in younger women.
authors.affiliation: Breast Cancer and the Environment Research Program, Department of Physiology, Michigan State University, Biomedical and Physical Sciences Building, Room 2201, 567 Wilson Road, East Lansing, MI, 48824, USA. aupperl4@msu.edu.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Aupperlee
authors.affiliation: Breast Cancer and the Environment Research Program, Department of Physiology, Michigan State University, Biomedical and Physical Sciences Building, Room 2201, 567 Wilson Road, East Lansing, MI, 48824, USA. yzhao818@hotmail.com.|Present address: College of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University, Qingdao, 266109, People's Republic of China. yzhao818@hotmail.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Breast Cancer and the Environment Research Program, Department of Physiology, Michigan State University, Biomedical and Physical Sciences Building, Room 2201, 567 Wilson Road, East Lansing, MI, 48824, USA. yingsiow@gmail.com.|Present address: Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA. yingsiow@gmail.com.
authors.forename: Ying Siow
authors.initials: YS
authors.lastname: Tan
authors.affiliation: Breast Cancer and the Environment Research Program, Department of Physiology, Michigan State University, Biomedical and Physical Sciences Building, Room 2201, 567 Wilson Road, East Lansing, MI, 48824, USA. zhuyiron@msu.edu.
authors.forename: Yirong
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, MI, USA. langohr@msu.edu.|Present address: Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, 70803, USA. langohr@msu.edu.
authors.forename: Ingeborg M
authors.initials: IM
authors.lastname: Langohr
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. ekirk@email.unc.edu.
authors.forename: Erin L
authors.initials: EL
authors.lastname: Kirk
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. jrpirone@gmail.com.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Pirone
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. troester@unc.edu.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. troester@unc.edu.|Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. troester@unc.edu.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Troester
authors.affiliation: Breast Cancer and the Environment Research Program, Department of Microbiology and Molecular Genetics, Michigan State University, Biomedical and Physical Sciences Building, Room 2201, 567 Wilson Road, East Lansing, MI, 48824, USA. schwart9@msu.edu.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Schwartz
authors.affiliation: Breast Cancer and the Environment Research Program, Department of Physiology, Michigan State University, Biomedical and Physical Sciences Building, Room 2201, 567 Wilson Road, East Lansing, MI, 48824, USA. shaslam@msu.edu.
authors.forename: Sandra Z
authors.initials: SZ
authors.lastname: Haslam
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism*; D018196:Carcinoma, Adenosquamous / Q000209:etiology* / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D005260:Female; D008321:Mammary Glands, Animal / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000209:etiology* / Q000378:metabolism; D008807:Mice, Inbred BALB C; D012741:Sexual Maturation; D059467:Transcriptome; D051176:beta Catenin / Q000378:metabolism
chemical_list: C495267:CTNNB1 protein, mouse; D018925:Chemokines; D051176:beta Catenin