High animal fat diet (HFD) has long been suspected to increase breast cancer risk. Studies in human and rodents support the hypothesis that environmental exposure in puberty will affect breast cancer risk in adulthood. This study examined the effects of pubertal HFD in both obesity-prone FVB mice and obesity-resistant BALB/c mice. FVB mice were fed a high fat diet from three weeks of age and exposed to DMBA-induced carcinogenesis. The pubertally initiated HFD increased mammary tumor incidence, showed a trend toward recruitment of an increased number of macrophages to early hyperplastic lesions, and had no effects on proliferation or angiogenesis in FVB mice. Wild type BALB/c mice were transplanted with Trp53-null mammary epithelium. HFD restricted to puberty increased early tumor incidence over a 52-week time course, but not over a longer period. Life-long and adult HFD increased tumor incidence over a 70-week time course. Notably, adult HFD specifically increased the incidence of spindle cell carcinomas that resemble claudin-low, triple negative human breast cancer. Irrespective of histopathology, tumors that developed in mice fed life-long HFD, pubertal HFD, and adult HFD all showed enhanced tumor proliferation, angiogenesis and M2-type macrophage recruitment. HFD promotes mammary tumorigenesis independent of obesity. In addition to puberty, there may be multiple windows of susceptibility to HFD.
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