In this large sample of Hispanic and NHW women from the BCHDS, four polymorphisms, including rs7903146, and one haplotype were significantly associated with breast cancer risk after adjusting for multiple comparisons. Although we did not find significant interactions with ethnicity or by genetic admixture, our data suggest that the associations of rs3750804 and rs3814570 with breast cancer risk may be modified by diabetes history. Some associations may have been influenced by obesity and menopausal status also. Lastly, results suggest that the associations of several TCF7L2 polymorphisms and two haplotypes may differ by ER and PR status.
We evaluated the associations of the more-widely studied polymorphisms, rs7903146 and rs12255372, as well as 23 other SNPs to better characterize associations across the gene. Consistent with our findings, Naidu et al. reported that the T allele of rs12255372 (TT genotype, OR, 1.574; 95 % CI 0.829–2.987); GT/TT, OR, 1.365; 95 % CI 0.989–1.883) was not associated with risk of breast cancer. However, carriers of the rs7903146 T allele (OR, 1.316; 95 % CI 1.022–1.695) and CT/TT genotypes, (OR, 1.419; 95 % CI 1.027–1.960) had an increased risk [17
]. Burwinkel et al. [15
] examined the association of rs12255372 with familial breast cancer risk and reported that the T allele was significantly, positively associated (OR, 1.19; 95 % CI 1.01–1.42, p
= 0.04) [15
]. In contrast, Goode et al. [16
] found no overall association (OR, 1.04; 95 % CI 0.89–1.22) [16
]. However, in sub-group analyses, associations were observed in pre-menopausal women (OR, 1.46; 95 % CI 0.99–2.15; p
= 0.06), and those with HER2 positive (OR, 1.48; 95 % CI 1.00–2.01; p
= 0.05) or triple negative (OR, 2.01; 95 % CI 1.10–3.67; p
= 0.02) breast cancer [16
]. Although our study was unable to assess the association between TCF7L2
and HER2 positive or triple negative breast cancers, given incomplete data on HER2 status, results suggests that several of the polymorphisms and haplotypes were significantly associated with the ER−/PR− tumor phenotype.
Specific variants of TCF7L2
have been reported to be associated with risk of diabetes [2
]. Although the underlying mechanisms are unclear, studies suggest that the gene may regulate glucagon-like peptide 1 (GLP-1) through the Wnt-signaling pathway [5
]. The association between diabetes and breast cancer risk has received increased attention in epidemiological research, but findings are mixed [33
]. Based on the TCF7L2
gene’s influence on diabetes, and its potential to increase breast cancer risk, we tested for interaction effects between women who had a history of diabetes and women who did not. We did not find significant interaction effects for variants rs7903146 and rs12255372, the two SNPs that have been implicated as the major TCF7L2
polymorphisms associated with diabetes. However, we identified two other variants, rs3750804 and rs3814570, that could further be explored for associations with diabetes and breast cancer risk.
The mechanism underlying the association between TCF7L2
and breast cancer has not been established, although the Wnt/β
-catenin pathway has been implicated [9
]. In normal cells, the levels of free cytosolic β
-catenin are maintained, due to their degradation by the APC, AXIN and kinase GSK3β
complex. This multicomponent complex phosphorylates β
-catenin on N-terminal residues and targets the protein for ubiquitination and proteolysis [10
]. However, stimulation of the Wnt-pathway with a ligand inhibits the activity of the complex, and β
-catenin is less phosphorylated and ubiquitinated, leading to an accumulation of β
-catenin in the cytosol and increased entry of β
-catenin into the nucleus [10
]. Once in the nucleus, β
-catenin combines with transcription factors of the TCF/LEF1 family and forms a complex that stimulates the expression of certain target genes, including cyclin D1 and c-myc
]. Other target genes for TCF7L2
have been found for breast cancer including osteopontin (OPN), monocyte chemotactic protein-1 (MCP-1/CCL2), and RAD6B. OPN functions in neoplastic transformation, malignant cell attachment, and migration and high serum levels of OPN have been found to be associated with metastasis [1
Continuous stimulation of the Wnt-signaling pathway leads to APC mutations that result in increased expression of the β
-catenin protein and higher β
-catenin-Tcf transcriptional activity. Some have investigated the role of mutations in the β
-catenin, APC, and/or AXIN in breast cancer carcinogenesis, but few have reported significant results. The best evidence implicates mutations in APC [9
]. It is not clear if the mutations in the Wnt-signaling pathway components directly contribute to the β
-catenin levels, as increased levels of β
-catenin-Tcf transcriptional activity have been found in breast cancer cell lines [9
Our study has several strengths. It included a large sample size of over 3,500 cases and 4,200 controls from three population-based case–control studies conducted in the United States and Mexico, and 1,937 cases with available data on tumor hormone receptor status. Another important strength was the large number of Hispanic women included in the analyses. Previous studies with TCF7L2
and breast cancer did not include Hispanic women [15
]. In addition to evaluating ethnic differences in associations between Hispanics and NHWs, we were able to account for genetic admixture in our analyses. We previously demonstrated that women with more Native American versus more European ancestry have lower risk of breast cancer [18
]. Adjusting for genetic ancestry within admixed populations may also adjust for other underlying genetic factors that influence breast cancer risk.
While we accounted for multiple comparisons, this adjustment does not completely eliminate false positive associations. Therefore, replication of these results, particularly the interaction effects by diabetes history, is needed. Another limitation is the lack of tumor phenotype data for the Mexico Breast Cancer Study, which contributed 816 Hispanic cases and 994 Hispanic controls. Hispanic women with breast cancer are more likely to have ER−/PR− tumors [45
], and inclusion of these women in our multinomial logistic regression analysis might have strengthened our results by tumor phenotype.
In summary, using a tagSNP approach, our results suggest that there is a significant association between the TCF7L2 gene and risk of breast cancer regardless of ethnicity and/or Native American ancestry. A novel finding is potential effect modification by history of diabetes for TCF7L2 polymorphisms rs3750804 and rs3814570. We also identified several variants that may be associated with risk for the ER−/PR− tumor phenotype. Although we did not find significant interactions by Hispanic ethnicity or by genetic admixture, additional research is needed to elucidate factors that contribute to racial/ethnic disparities in breast cancer. Future research on breast cancer genetics should involve identifying genetic differences by race and ethnicity for breast cancer risk, prognosis, and survival. Such findings could illuminate new pathways for breast cancer treatment.