Abstract LB-21: Growth factor genes and change in mammographic density after quitting estrogen and progestin hormone therapy in the California Teachers Study.
Authors: Lee Eunjung , Schumacher Fred , Wu Anna H. , Bernstein Leslie , Ursin Giske 
Published: August 2014

Abstract
Mammographic density (MD), a measure of the amount of epithelium and stroma in the breast, is a strong risk factor for breast cancer. Estrogen and progestin therapy (EPT) in postmenopausal women increases women's breast cancer risk. Although MD increases following EPT use and decreases following EPT cessation, substantial inter-individual variation in EPT-related MD changes is observed. Recent findings suggest that lifestyle factors do not explain much of the variation in the MD decrease following EPT cessation, suggesting that genetic factors could be major determinants. However, few studies have investigated genetic predictors of EPT-associated MD change. EPT increases breast cell proliferation, and activation of growth factor signaling pathways, such as epidermal growth factor and insulin-like growth factor 1 (IGF-1), may be required for estrogen-dependent cell proliferation. Therefore, we hypothesized that polymorphisms in growth factor genes are associated with EPT-related MD change. Using data from a mammogram substudy of the California Teachers Study, we investigated the association between 196 single nucleotide polymorphisms (SNPs) in 13 growth factor genes and MD changes after quitting EPT use. We studied genotypes and longitudinal MD data obtained before and after quitting EPT in 284 non-Hispanic white women. The median time interval between the two mammograms was 4 years (range: 1-9 years). We determined the MD (as percent MD) using a previously validated computer-assisted program. We used linear regression models to estimate the difference in MD between the ‘on-EPT’ and ‘off-EPT’ mammograms, adjusting for age and body mass index (BMI) at on-EPT mammogram, time interval and BMI change between the two mammograms, and baseline MD. After adjusting for multiple testing within each gene, we observed statistically significant associations for rs1983210 in INHA (P values adjusted for multiple correlated tests within a gene (Padj) = 0.021) and rs35539615 in IGFBP1/3 (Padj = 0.042) in relation to change in MD. The estimated differences in MD change per minor allele of these SNPs were -1.80% and 1.79%, respectively. In addition, rs2278200 in INHA showed some evidence of association with borderline statistical significance (Padj =0.053). Functional significance of these SNPs in regulating expression levels of INHA and IGFBP1/3 is not known. INHA encodes the alpha subunit of inhibins A and B, which are involved in cell differentiation and proliferation, and have been found to be expressed in the breast tissue. IGFBP1 and IGFBP3 are important regulators of bioavailability of IGF-1, which has been shown to stimulate proliferation of breast cancer cell lines in synergy with estrogen. While our findings require replication, our results suggest that genetic variation in these growth factor genes may influence MD change following EPT cessation.
Citation Format: Eunjung Lee, Fred Schumacher, Anna H. Wu, Leslie Bernstein, Giske Ursin. Growth factor genes and change in mammographic density after quitting estrogen and progestin hormone therapy in the California Teachers Study. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-21. doi:10.1158/1538-7445.AM2013-LB-21
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.