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01.08.2011 | Research article | Ausgabe 4/2011 Open Access

Breast Cancer Research 4/2011

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

Zeitschrift:
Breast Cancer Research > Ausgabe 4/2011
Autoren:
Petra EA Huijts, Minka van Dongen, Moniek CM de Goeij, Adrian J van Moolenbroek, Freek Blanken, Maaike PG Vreeswijk, Esther M de Kruijf, Wilma E Mesker, Erik W van Zwet, Rob AEM Tollenaar, Vincent THBM Smit, Christi J van Asperen, Peter Devilee
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:https://​doi.​org/​10.​1186/​bcr2917) contains supplementary material, which is available to authorized users.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

The experiments were performed by PH, MD, MG and AM. The patient material was provided by RT and VS. The cells were cultured by FB and MV. The stroma percentage of 50 tumors was analyzed by EK and WM. The experiments were designed, analyzed and interpreted by PH, CA and PD. EZ helped with the statistical analyses and the interpretation of the data. The manuscript was drafted by PH and critically revised by MV, CA and PD. All authors read and approved the final manuscript.

Abstract

Introduction

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.

Methods

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.

Results

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.

Conclusions

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.
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