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.