FGFR2 and MAP3K1 are members of the RAS/RAF/MEK/ERKsignaling 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 populationbased case-control sample of 1225 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 (ER1), progesterone receptor-positive (PR1) and HER2/Neu-negative (HER22) tumors. MAP3K1 was not associated with breast cancer in EA women, but it was associated with breast cancer in AA women, again limited to ER1, PR1 and HER22 tumors. An interaction was observed between combined hormone replacement therapy use and FGFR2 rs1219648 genotypes on breast cancer risk in EA women (P 5 0.010). Finally, we observed a significant interaction between MAP3K1 rs889312 and FGFR2 rs2981582 (P 5 0.022) in AA but not EAwomen. These results confirm that FGFR2 and MAP3K1 are involved in breast cancer susceptibility and confer their effects primarily in ER1 and PR1 tumors. We further report that these genes confer their effects in HER22 tumors, interact with one another to confer breast cancer susceptibility in AA women and interact with hormone exposures in AA and EA women.

Inherited BRCA1 mutations confer elevated breast cancer risk. Recent studies have identified genes that encode proteins that interact with BRCA1 as modifiers of BRCA1-associated breast cancer. We evaluated a comprehensive set of genes that encode most known BRCA1 interactors to evaluate the role of these genes as modifiers of cancer risk. A cohort of 2,825 BRCA1 mutation carriers was used to evaluate the association of haplotypes at ATM, BRCC36, BRCC45 (BRE), BRIP1 (BACH1/FANCJ), CTIP, ABRA1 (FAM175A), MERIT40, MRE11A, NBS1, PALB2 (FANCN), RAD50, RAD51, RAP80, TOPBP1 and time to breast and ovarian cancer diagnosis. False Discovery Rate (FDR) adjusted p-value for overall association of haplotypes (pFDR) with breast cancer were identified at ATM (pFDR =0.029), BRCC45 (pFDR=0.0.19), BRIP1 (pFDR =0.008), CTIP (pFDR =0.017), MERIT40 (pFDR =0.019), NBS1 (pFDR=0.003), RAD50 (pFDR=0.014), and TOPBP1 (pFDR =0.011) and were associated with breast cancer risk. Haplotypes at ABRA1 (pFDR=0.007), BRCC45 (pFDR=0.016 and pFDR=0.005 in two haplotype blocks) and RAP80 (pFDR<0.001) were associated with ovarian cancer risk. Overall, the data suggest that genomic variation at multiple loci that encode proteins that interact biologically with BRCA1 are associated with modified breast cancer and ovarian cancer risk in women who carry BRCA1 mutations.