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PMID: 21767389 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

Allele-specific regulation of FGFR2 expression is cell type-dependent and may increase breast cancer risk through a paracrine stimulus involving FGF10.

Breast cancer research : BCR ·Vol. 13 ·No. 4 ·2011-07-18 ·Pages R72

Huijts PE, van Dongen M, de Goeij MC, van Moolenbroek AJ, Blanken F, Vreeswijk MP, de Kruijf EM, Mesker WE, van Zwet EW, Tollenaar RA, Smit VT, van Asperen CJ, Devilee P

Abstract

SNPs rs2981582 and rs2981578, located in a linkage disequilibrium block (LD block) within intron 2 of the fibroblast growth factor receptor 2 gene (FGFR2), are associated with a mildly increased breast cancer risk. Allele-specific regulation of FGFR2 mRNA expression has been reported previously, but the molecular basis for the association of these variants with breast cancer has remained elusive to date. mRNA levels of FGFR2 and three fibroblast growth factor genes (FGFs) were measured in primary fibroblast and epithelial cell cultures from 98 breast cancer patients and correlated to their rs2981578 genotype. The phosphorylation levels of downstream FGFR2 targets, FGF receptor substrate 2α (FRS2α) and extracellular signal-regulated kinases 1 and 2 (ERK1/2), were quantified in skin fibroblasts exposed to FGF2. Immunohistochemical markers for angiogenesis and lymphocytic infiltrate were semiquantitatively assessed in 25 breast tumors. The risk allele of rs2981578 was associated with increased FGFR2 mRNA levels in skin fibroblasts, but not in skin epithelial cell cultures. FGFR2 mRNA levels in skin fibroblasts and breast fibroblasts correlated strongly in the patients from whom both cultures were available. Tumor-derived fibroblasts expressed, on average, eight times more FGFR2 mRNA than the corresponding fibroblasts from normal breast tissue. Fibroblasts with higher FGFR2 mRNA expression showed more FRS2α and ERK1/2 phosphorylation after exposure to FGF2. In fibroblasts, higher FGFR2 expression correlated with higher FGF10 expression. In 25 breast tumors, no associations between breast tumor characteristics and fibroblast FGFR2 mRNA levels were found. The influence of rs2981578 genotypes on FGFR2 mRNA expression levels is cell type-dependent. Expression differences correlated well with signaling levels of the FGFR2 pathway. Our results suggest that the increased breast cancer risk associated with SNP rs2981578 is due to increased FGFR2 signaling activity in stromal fibroblasts, possibly also involving paracrine FGF10 signaling.

MeSH Terms
Adaptor Proteins, Signal Transducing/metabolism Aged Alleles Breast Neoplasms/genetics,metabolism,pathology Epithelial Cells/metabolism Female Fibroblast Growth Factor 10/genetics,metabolism Fibroblasts/metabolism,pathology Gene Expression Regulation, Neoplastic Genetic Predisposition to Disease Humans Membrane Proteins/metabolism Middle Aged Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3/metabolism Polymorphism, Single Nucleotide Receptor, Fibroblast Growth Factor, Type 2/genetics,metabolism Reference Values Signal Transduction Skin/cytology,metabolism Stromal Cells/metabolism
Chemicals
Adaptor Proteins, Signal Transducing FGF10 protein, human FRS2 protein, human Fibroblast Growth Factor 10 Membrane Proteins FGFR2 protein, human Receptor, Fibroblast Growth Factor, Type 2 MAPK1 protein, human Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Huijts Petra E A
Department of Clinical Genetics, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. p.e.a.huijts@lumc.nl
van Dongen Minka
de Goeij Moniek C M
van Moolenbroek Adrian J
Blanken Freek
Vreeswijk Maaike P G
de Kruijf Esther M
Mesker Wilma E
van Zwet Erik W
Tollenaar Rob A E M
Smit Vincent T H B M
van Asperen Christi J
Devilee Peter
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Article Info
Journal
Breast cancer research : BCR
Abbr.
Breast Cancer Res
ISSN
1465-542X
DOI
10.1186/bcr2917
Email
p.e.a.huijts@lumc.nl
Published
2011-07-18
Epub
2011-00-18
Pages
R72
Language
English
Region
England
NLM ID
100927353
PMCID
PMC3236336
Subset
IM
External Links
PubMed source DOI: 10.1186/bcr2917 PMC Full Text View journal details
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