Dietary fat alters pulmonary metastasis of mammary cancers through cancer autonomous and non-autonomous changes in gene expression |
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Authors: | Michele La Merrill Ryan R Gordon Kent W Hunter David W Threadgill " target="_blank">Daniel Pomp |
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Institution: | (1) Department of Preventive Medicine, Mount Sinai School of Medicine, Box 1057, New York, NY 10029, USA;(2) Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA;(3) Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA;(4) Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA;(5) Laboratory of Cancer Biology and Genetics, NIH/NCI, Bethesda, MD 20892, USA;(6) Center for Environmental Health and Susceptibility, Lineberger Cancer Center and Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA |
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Abstract: | 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. |
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