FGFR2 intronic SNPs and breast cancer risk: Associations with tumor characteristics and interactions with exogenous exposures and other known breast cancer risk factors
Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057-1465, USA. International Journal of Cancer
(Impact Factor: 5.09).
08/2011; 129(3):702-12. DOI: 10.1002/ijc.25686
Recent genome-wide association studies have revealed several new candidate genes for breast cancer, including fibroblast growth factor receptor 2 (FGFR2) gene. The associations were also replicated in several other independent studies. The next important step is to study whether these common variants interact with known breast cancer risk factors, exogenous exposures and tumor characteristics. In a population-based case-control study of 1,170 breast cancer cases and 2,115 controls, we examined genetic associations of four intronic FGFR2 single-nucleotide polymorphisms (SNPs) and breast tumor characteristics and assessed the potential interactions with smoking, alcohol consumption, adiposity and known breast cancer risk factors. FGFR2 variants were significantly associated with breast cancer risk regardless of estrogen and progesterone receptor status, metastasis, lymph node involvement and histologic and nuclear grade. The FGFR2-breast cancer association was modified by smoking status, with increased risk for former and current smokers compared to never smokers; former/current smokers carrying two copies of the rs1219648 minor allele were at highest risk with a crude OR (95% confidence interval) of 2.11 (1.52-2.92) compared to never smokers with no rs1219648 variant alleles. Our study found no evidence for either modification of FGFR2 and breast cancer by alcohol intake or adiposity, even when analyses were stratified by menopausal status. Although these results require further replication, they may provide new insight into the possible new exposures that may interact with FGFR2 susceptibility alleles.
Available from: Cecilia Perez Piñero
[Show abstract] [Hide abstract]
ABSTRACT: Fibroblast growth factor receptors (FGFRs) are tyrosine kinase receptors which have been implicated in breast cancer. The aim of this study was to evaluate FGFR-1, -2, -3, and -4 protein expressions in normal murine mammary gland development, and in murine and human breast carcinomas. Using immunohistochemistry and Western blot, we report a hormonal regulation of FGFR during postnatal mammary gland development. Progestin treatment of adult virgin mammary glands resulted in changes in localization of FGFR-3 from the cytoplasm to the nucleus, while treatment with 17-β-estradiol induced changes in the expressions and/or localizations of FGFR-2 and -3. In murine mammary carcinomas showing different degrees of hormone dependence, we found progestin-induced increased expressions, mainly of FGFR-2 and -3. These receptors were constitutively activated in hormone-independent variants. We studied three luminal human breast cancer cell lines growing as xenografts, which particularly expressed FGFR-2 and -3, suggesting a correlation between hormonal status and FGFR expression. Most importantly, in breast cancer samples from 58 patients, we found a strong association (P < 0.01; Spearman correlation) between FGFR-2 and -3 expressions and a weaker correlation of each receptor with estrogen receptor expression. FGFR-4 correlated with c-erbB2 over expression. We conclude that FGFR-2 and -3 may be mechanistically linked and can be potential targets for treatment of estrogen receptor-positive breast cancer patients.
Breast Cancer Research and Treatment 11/2011; 133(3):997-1008. DOI:10.1007/s10549-011-1883-6 · 3.94 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Fibroblast growth factor receptor 2 (FGFR2) is a member of a receptor tyrosine kinase gene superfamily, involved in cell growth, invasiveness, motility, and angiogenesis, which has attracted considerable attention as a candidate gene for breast cancer (BC) since it was first identified through genome-wide association approach. In the past few years, the relationship between FGFR2 and BC has been reported in various ethnic groups; however, these studies have yielded contradictory results. To investigate this inconsistency, we performed a meta-analysis of 37 studies involving a total of 288,142 subjects for rs2981582, rs1219648, and rs2420946 polymorphism of the FGFR2 gene to evaluate the effect of FGFR2 on genetic susceptibility for BC. Overall, significantly increased BC risk was associated with these polymorphisms when all studies were pooled into the meta-analysis. In addition, our data indicate that FGFR2 is involved in BC susceptibility and confer its effect primarily in estrogen receptor-positive and progesterone receptor-positive tumors. When stratified by ethnicity, significantly increased risks were found in Caucasian and East Asian populations. However, no significant associations were detected among African descent populations. There was strong evidence of heterogeneity (P < 0.05), which largely disappeared after stratification by ethnicity. This meta-analysis demonstrated that FGFR2 polymorphism is a risk factor associated with increased BC susceptibility, but these associations vary in different ethnic populations.
Breast Cancer Research and Treatment 11/2012; 137(2). DOI:10.1007/s10549-012-2343-7 · 3.94 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Fibroblast growth factors (FGFs) signal through FGF receptors (FGFRs), which are a sub-family of the superfamily of receptor tyrosine kinases, to regulate human development and metabolism. Uncontrolled FGF signaling is responsible for diverse array of developmental disorders, most notably skeletal syndromes due to FGFR gain-of-function mutations. Studies in the last few years have provided significant evidence for the importance of FGF signaling in the pathogenesis of diverse cancers, including endometrial and bladder cancers. FGFs are both potent mitogenic and angiogenic factors and can contribute to carcinogenesis by stimulating cell proliferation and tumor angiogenesis. Gene knockout and pharmacological inhibition of FGFRs in in vivo and in vitro models validate FGFRs as a target for cancer treatment. Considerable efforts are being expended to develop specific, small-molecule inhibitors for treating FGFR-driven cancers. Recent reviews on the FGF/FGFR system have focused primarily on signaling, pathophysiology, and functions in cancer. In this article, we review the key roles of FGFR in cancer, provide an update on the status of clinical trials with small-molecule FGFR inhibitors, and discuss how the current structural data on FGFR kinases guide the design and characterization of new FGFR inhibitors.
Cytokine & growth factor reviews 07/2013; 24(5). DOI:10.1016/j.cytogfr.2013.05.002 · 5.36 Impact Factor
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.