Clinical & Experimental Metastasis

, Volume 27, Issue 2, pp 107–116

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

  • Michele La Merrill
  • Ryan R. Gordon
  • Kent W. Hunter
  • David W. Threadgill
  • Daniel Pomp
Research Paper

DOI: 10.1007/s10585-009-9302-7

Cite this article as:
La Merrill, M., Gordon, R.R., Hunter, K.W. et al. Clin Exp Metastasis (2010) 27: 107. doi:10.1007/s10585-009-9302-7

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.

Keywords

Btn1a1 eQTL Mammary cancer Nutrigenomics Pulmonary metastasis PyMT 

Abbreviations

AMD

Average pulmonary metastatic density

AKT

Thymoma viral proto-oncogene

BMI

Body mass index

BTN1A1

Butyrophilin, subfamily 1, member A1

CTNNB1

Catenin (cadherin associated protein) beta 1

EDNRB

Endothelin receptor type B

EIF4EBP1

Eukaryotic translation initiation factor 4E binding protein 1

ENPP2

Ectonucleotide pyrophosphatase/phosphodiesterase 2

eQTL

Expression quantitative trait locus

F2

Filial 2

HDAC

Histone deacetylase

HFD

High fat diet

IL1b

Interleukin 1β

IPA

Ingenuity pathways analysis

IPAKB

Ingenuity pathways analysis knowledge base

MCD

Matched control diet

MET

Superficial pulmonary metastasis

MMP

Matrix metallopeptidase

MMTV-PyMT

FVB/N-Tg(MMTV-PyVT)634Mul/J

MON1A

MON1 homolog A

NADH

Nicotinamide adenine dinucleotide

NDRG1

N-myc downstream regulated gene 1

NFKB

Nuclear factor of kappa light polypeptide gene enhancer in B-cells

P

P-value

PI3K

Phosphatidylinositol 3-kinase

PTEN

Phosphatase and tensin homolog

QTL

Quantitative trait loci

RNA

Ribonucleic acid

SAA

Serum amyloid A

SNP

Single nucleotide polymorphism

TIMP1

Tissue inhibitor of metalloproteinase 1

TNFα

Tumor necrosis factor alpha

VEGF

Vascular endothelial grow factor

XDH

Xanthine dehydrogenase

Supplementary material

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • Michele La Merrill
    • 1
    • 2
    • 3
  • Ryan R. Gordon
    • 4
  • Kent W. Hunter
    • 5
  • David W. Threadgill
    • 2
    • 3
    • 6
  • Daniel Pomp
    • 2
    • 3
    • 4
    • 6
  1. 1.Department of Preventive MedicineMount Sinai School of MedicineNew YorkUSA
  2. 2.Curriculum in ToxicologyUniversity of North Carolina at Chapel HillChapel HillUSA
  3. 3.Department of GeneticsUniversity of North Carolina at Chapel HillChapel HillUSA
  4. 4.Department of NutritionUniversity of North Carolina at Chapel HillChapel HillUSA
  5. 5.Laboratory of Cancer Biology and GeneticsNIH/NCIBethesdaUSA
  6. 6.Center for Environmental Health and Susceptibility, Lineberger Cancer Center and Carolina Center for Genome SciencesUniversity of North Carolina at Chapel HillChapel HillUSA