Pubertal and adult windows of susceptibility to a high animal fat diet in Trp53-null mammary tumorigenesis

// Yirong Zhu 1 , Mark D. Aupperlee 2 , Yong Zhao 2 , Ying Siow Tan 2 , Erin L. Kirk 4 , Xuezheng Sun 4 , Melissa A. Troester 4, 5, 6 , Richard C. Schwartz 3 , Sandra Z. Haslam 2 1 Cell and Molecular Biology Program and Breast Cancer and the Environment Research Program, Michigan State University, East Lansing, MI, USA 2 Department of Physiology and Breast Cancer and the Environment Research Program, Michigan State University, East Lansing, MI, USA 3 Department of Microbiology and Molecular Genetics and Breast Cancer and the Environment Research Program, Michigan State University, East Lansing, MI, USA 4 Department of Epidemiology, University of North Carolina at Chapel Hill, NC, USA 5 Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, NC, USA 6 Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, NC, USA Correspondence to: Sandra Z. Haslam, email: shaslam@msu.edu Richard C. Schwartz, email: schwart9@msu.edu Keywords: dietary animal fat, breast cancer, puberty, adulthood, Trp53-null Received: July 22, 2016      Accepted: October 19, 2016      Published: November 04, 2016 ABSTRACT 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.