Pubertal and adult windows of susceptibility to a high animal fat diet in Trp53-null mammary tumorigenesis.
Premenopausal breast cancer is associated with increased animal fat consumption among normal weight, but not overweight women (Farvid et al., 2014). Our previous findings in obesity-resistant BALB/c mice similarly showed promotion of carcinogen-induced mammary tumorigenesis by a diet high in saturated animal fat (HFD). This effect was specific to pubertal versus adult HFD. This study identifies the effects of HFD during puberty versus adulthood in Trp53-null transplant BALB/c mice and investigates its mechanism of enhancing tumorigenesis. Either pubertal or adult HFD is sufficient to increase incidence of Trp53-null mammary tumors. Puberty-restricted HFD exposure promoted tumor cell proliferation, increased angiogenesis, and increased recruitment of total and M2 macrophages in epithelial tumors. Adult-restricted exposure to HFD similarly increased proliferation, angiogenesis, recruitment of total and M2 macrophages, and additionally reduced apoptosis. Adult HFD also increased incidence of spindle cell carcinomas resembling claudin-low breast cancer, and thus adult HFD in the Trp53-null transplantation system may be a useful model for human claudin low breast cancer. Importantly, these results on Trp53-null and our prior studies on DMBA-induced mammary tumorigenesis demonstrate a pubertal window of susceptibility to the promotional effects of HFD, indicating the potential of early life dietary intervention to reduce breast cancer risk.
Cell and Molecular Biology Program and Breast Cancer and the Environment Research Program, Michigan State University, East Lansing, MI, USA.
Yirong
Y
Zhu
Department of Physiology and Breast Cancer and the Environment Research Program, Michigan State University, East Lansing, MI, USA.
Mark D
MD
Aupperlee
Department of Physiology and Breast Cancer and the Environment Research Program, Michigan State University, East Lansing, MI, USA.
Yong
Y
Zhao
Department of Physiology and Breast Cancer and the Environment Research Program, Michigan State University, East Lansing, MI, USA.
Ying Siow
YS
Tan
Department of Epidemiology, University of North Carolina at Chapel Hill, NC, USA.
Erin L
EL
Kirk
Department of Epidemiology, University of North Carolina at Chapel Hill, NC, USA.
Xuezheng
X
Sun
Department of Epidemiology, University of North Carolina at Chapel Hill, NC, USA.|Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC, USA.|Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, NC, USA.
Melissa A
MA
Troester
Department of Microbiology and Molecular Genetics and Breast Cancer and the Environment Research Program, Michigan State University, East Lansing, MI, USA.
Richard C
RC
Schwartz
Department of Physiology and Breast Cancer and the Environment Research Program, Michigan State University, East Lansing, MI, USA.
Sandra Z
SZ
Haslam
D000367:Age Factors; D000818:Animals; D017209:Apoptosis; D002277:Carcinoma / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D059305:Diet, High-Fat / Q000009:adverse effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008321:Mammary Glands, Animal / Q000378:metabolism* / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic; D010641:Phenotype; D012307:Risk Factors; D046468:Sexual Development; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics
D016159:Tumor Suppressor Protein p53
Trp53-null; adulthood; breast cancer; dietary animal fat; puberty