Abstract LB-294: Growth factor genes, interaction with hormone therapy use and breast cancer risk in the California Teachers Study
Authors: Lee Eunjung , Schumacher Fredrick , Neuhausen Susan L. , Culver Hoda Anton , Ziogas Argyrios , Berg David Van Den , Bernstein Leslie , Ursin Giske 
Published: May 2015

Background: Growth factor and angiogenesis pathway genes are important candidate genes in breast carcinogenesis. Breast cell proliferation is modified by exogenous hormone therapy (HT) use, particularly estrogen plus progestin therapy (EPT). Estrogen-dependent cell proliferation requires activation of growth factor pathways, such as IGF-1, and potential interactions between a few FGFR2 single nucleotide polymorphisms (SNPs) and EPT have been reported. Further, angiogenesis genes such as VEGF and EGR3 were shown to be induced by steroid hormones. Therefore, we investigated SNPs in growth factor and angiogenesis genes and their interaction with HT in relation to breast cancer risk.

Methods: We analyzed data from a breast cancer case-control study nested within the California Teachers Study. We genotyped 202 tagging SNPs in 12 growth factor and angiogenesis genes in 2746 non-Hispanic white women: 1351 cases and 1395 controls. We used conditional logistic regression models to estimate odds ratios (ORs) per minor allele and 95% confidence intervals (CI), and we repeated the analyses separately by HT use at cohort enrollment. P values were corrected for multiple testing using the Bonferroni method (Padj).

Results: The most significant associations were observed for rs6899540 in VEGFA and 3 other VEGFA SNPs that are not in linkage disequilibrium with rs6899540. After Bonferroni correction within this gene, only rs6899540, located 4kb distal of the 3’end of the gene, remained statistically significant: OR per C allele=1.27 (95% CI=1.10-1.47), P=0.001, Padj=0.020. Additional SNPs nominally associated with breast cancer risk included rs2072454 in EGFR, rs4970503 in RPS6KA1, and rs9580185 in FGF9. Analyses among postmenopausal EPT users identified nominal associations with 5 VEGFR3 SNPs including rs6889643 and rs2290983 (ORs per risk allele ranging from 1.28 to 1.46; P-values range 0.008-0.015). Although none of these associations were statistically significant after Bonferroni correction, P values for interaction with EPT use (vs. never-HT use) were 0.03 for both rs6889643 and rs2290983. Among ET users, rs308441 in FGF2 was significantly associated with breast cancer risk (OR=1.69, Padj=0.019).

Conclusions: Our results suggest that SNPs in growth factor and VEGF pathways may be associated with breast cancer risk, and these associations may be modified by ET or EPT use. Of particular interest are potential gene-HT interactions for SNPs in VEGFA, a key player in angiogenesis, and FGF2, a gene involved in VEGF signaling. Our results provide a strong rationale for further exploring these pathways and potential gene-environment interactions in pooled analyses.

Citation Format: Eunjung Lee, Fredrick Schumacher, Susan L. Neuhausen, Hoda Anton Culver, Argyrios Ziogas, David Van Den Berg, Leslie Bernstein, Giske Ursin. Growth factor genes, interaction with hormone therapy use and breast cancer risk in the California Teachers Study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-294. doi:10.1158/1538-7445.AM2014-LB-294