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

Metastasis virulence, a significant contributor to breast cancer prognosis, is influenced by environmental factors like diet. We previously demonstrated in an F2 mouse population generated from a cross between the M16i polygenic obese and MMTV-PyMT mammary cancer models that high fat diet (HFD) decreases mammary cancer latency and increases pulmonary metastases compared to a matched control diet (MCD). Genetic analysis detected eight modifier loci for pulmonary metastasis, and diet significantly interacted with all eight loci. Here, gene expression microarray analysis was performed on mammary cancers from these mice. Despite the substantial dietary impact on metastasis and its interaction with metastasis modifiers, HFD significantly altered the expression of only five genes in mammary tumors; four of which, including serum amyloid A (Saa), are downstream of the tumor suppressor PTEN. Conversely, HFD altered the expression of 211 hepatic genes in a set of tumor free F2 control mice. Independent of diet, pulmonary metastasis virulence correlates with mammary tumor expression of genes involved in endocrine cancers, inflammation, angiogenesis, and invasion. The most significant virulence-associated network harbored genes also found in human adipose or mammary tissue, and contained upregulated Vegfa as a central node. Additionally, expression of Btn1a1, a gene physically located near a putative cis-acting eQTL on chromosome 13 and one of the metastasis modifiers, correlates with metastasis virulence. These data support the existence of diet-dependent and independent cancer modifier networks underlying differential susceptibility to mammary cancer metastasis and suggest that diet influences cancer metastasis virulence through tumor autonomous and non-autonomous mechanisms.