Carcinogenesis Advance Access published online on November 20, 2008
Carcinogenesis, doi:10.1093/carcin/bgn247
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Hormone-Dependent Effects of FGFR2 and MAP3K1 in Breast Cancer Susceptibility in a Population-Based Sample of Postmenopausal African American and European American Women
1 Abramson Cancer Center
2 Department of Medicine
3 Center for Clinical Epidemiology and Biostatistics and Department of Biostatistics and Epidemiology, The University of Pennsylvania School of Medicine
4 Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA., Department of Pediatrics, The University of Pennsylvania School of Medicine
Corresponding Author: Timothy R. Rebbeck, Ph.D., Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, 904 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104-6021, Tel: 215-898-1793, Fax: 215-573-2265, Email: rebbeck{at}mail.med.upenn.edu
FGFR2 and MAP3K1 are members of the RAS/RAF/MEK/ERK signaling pathway and have been identified from genome-wide association studies to be breast cancer susceptibility genes. Potential interactions of these genes and their role with respect to tumor markers, hormonal factors, and race on breast cancer risk have not been explored. We examined FGFR2 and MAP3K1 variants, breast tumor characteristics, and hormone exposures in a population-based case-control sample of 1,225 European American (EA) and 584 African American (AA) women. FGFR2 rs1219648 and rs2981582 genotypes were significantly associated with breast cancer in EA only in estrogen receptor positive (ER+), progesterone receptor positive (PR+) and HER2/Neu negative (HER2-) tumors. MAP3K1 was not associated with breast cancer in EA women, but it was associated with breast cancer in AA women, again limited to ER+, PR+, and HER2- tumors. An interaction was observed between combined hormone replacement therapy use and FGFR2 rs1219648 genotypes on breast cancer risk in EA women (p = 0.010). Finally we observed a significant interaction between MAP3K1 rs889312 and FGFR2 rs2981582 (p = 0.022) in AA but not EA women. These results confirm that FGFR2 and MAP3K1 are involved in breast cancer susceptibility and confer their effects primarily in ER+ and PR+ tumors. We further report that these genes confer their effects in HER2- tumors, interact with one another to confer breast cancer susceptibility in AA women, and interact with hormone exposures in AA and EA women.
Key Words: Breast Cancer • steroid hormones • FGFR2 • MAP3K1
Received September 15, 2008; revised October 21, 2008; accepted October 23, 2008.
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