Genotype × diet interactions in mice predisposed to mammary cancer: II. Tumors and metastasis

Abstract

High dietary fat intake and obesity may increase the risk of susceptibility to certain forms of cancer. To study the interactions of dietary fat, obesity, and metastatic mammary cancer, we created a population of F(2) mice cosegregating obesity QTL and the MMTV-PyMT transgene. We fed the F(2) mice either a very high-fat or a matched-control-fat diet, and we measured growth, body composition, age at mammary tumor onset, tumor number and severity, and formation of pulmonary metastases. SNP genotyping across the genome facilitated analyses of QTL and QTL x diet interaction effects. Here we describe effects of diet on mammary tumor and metastases phenotypes, mapping of tumor/metastasis modifier genes, and the interaction between dietary fat levels and effects of cancer modifiers. Results demonstrate that animals fed a high-fat diet are not only more likely to experience decreased mammary cancer latency but increased tumor growth and pulmonary metastases occurrence over an equivalent time. We identified 25 modifier loci for mammary cancer and pulmonary metastasis, likely representing 13 unique loci after accounting for pleiotropy, and novel QTL x diet interactions at a majority of these loci. These findings highlight the importance of accurately modeling not only the human cancer characteristics in mice but also the environmental exposures of human populations.

High-fat Diet Enhances Mammary Tumorigenesis and Pulmonary Metastasis and Alters Inflammatory and Angiogenic Profiles in MMTV-PyMT Mice

“…Our results that the high-fat diet prolonged primary tumor latency do not agree with reports that a high-fat diet shortens or does not affect primary tumor latency (28,49). This disagreement may be caused by experimental differences, e.g.…”

“…This disagreement may be caused by experimental differences, e.g. animal models used (49), or methods to assess the latency (28). Nevertheless, the prolonged latency did not attenuate the tumorigenic enhancement by the high-fat diet, evidenced by the increased primary tumor burden and lung metastases.…”

Mouse breast cancer model-dependent changes in metabolic syndrome-associated phenotypes caused by maternal dioxin exposure and dietary fat

“…We observed that age-dependent differences in percent body fat due to diet, consistent with reports that the DMBA, PyMT, and HER2 models are sensitive to dietary fat and obesity (12,14,29). We did not observe any dietary effects on FVB control body weight or percent body fat, as expected, based on the literature (30).…”

Dietary fat alters pulmonary metastasis of mammary cancers through cancer autonomous and non-autonomous changes in gene expression

“…PyMT develops aggressive mammary tumors with subsequent pulmonary metastasis and has primary tumor gene expression similar to the gene expression of luminal breast tumors in women [12,13]. Mice from the resulting F2 mouse population co-segregating obesity quantitative trait loci (QTL) and the MMTV-PyMT transgene when fed a high fat diet (HFD) compared to those fed a matched control diet (MCD) had 8.6% increased body weight, 21.8% increased total body fat, decreased mammary cancer latency (3 days), 1.5 times larger mammary tumors, and 46-68% increased pulmonary metastases (dependent on method of measurement) [10,11]. These substantial diet effects were seen despite that F2 mice on either diet were heavier than PyMT on these same diets [14].…”

“…In order to examine mechanisms underlying the interaction of obesity with breast cancer and its metastasis, we developed an obese mouse model of breast cancer metastasis by crossing M16i, a polygenic obesity line, with FVB/ NJ-TgN(MMTV-PyMT) 634Mul (PyMT) [10,11]. PyMT develops aggressive mammary tumors with subsequent pulmonary metastasis and has primary tumor gene expression similar to the gene expression of luminal breast tumors in women [12,13].…”