Functional Igf1r Variant Predicts Preeclampsia Protection From Invasive Breast Cancer: Novel California Teachers Study Findings

Many studies have reported lower breast cancer risk in women who develop hypertension in pregnancy with a meta-analysis reporting hazard ratios of 0.86 for preeclampsia and 0.83 for gestational hypertension. Our prior work in the Marin Women9s Study (MWS) demonstrated both a lower breast density and a lower risk of breast cancer in women with pregnancy-induced hypertension (PIH) if they possess the TT genotype of IGF1R SNP rs2016347. The current study was designed to validate and expand upon these findings in the larger California Teachers Study (CTS) which consists of u003e130,000 female educators. From original participants a case-control study was established in 2012 consisting of all non-Hispanic white women with DNA samples that became cases since entry into the study (N = 2030) and controls without invasive or in situ breast cancer (N = 1552). The current study nests within this case control study. All participants with a self-reported history of preeclampsia were selected (81 cases/56 controls). IGF1R SNP rs2016347 was assessed by Taqman assay. Results: Women with the TT genotype had an odds ratio (OR) of 0.38 when compared to the GG genotype after adjusting for potential confounders. Stratification by HR+/HR- cases and by age of first birth (AFB) resulted in statistically significant adjusted OR9s of 0.26 for HR+ positive cases and 0.15 for women with AFB Overall in the CTS, the adjusted hazard ratio for women with vs without preeclampsia was 0.94 (0.81, 1.08). Conclusions: These results suggest significant breast cancer protection in women with preeclampsia that possess the TT genotype, specifically in those women with AFB IGF1R variant. Recent studies have associated the rs2016347 T allele with lower normal tissue expression of IGF1R mRNA, better survival in HR+ breast cancer, and improved pathological response to neoadjuvant chemotherapy. The protective T allele creates a new microRNA (miR-432) binding site within the IGF1R 39UTR, offering a potential functional explanation for reduced mammary gland expression of this cancer-associated growth factor. This may interact with alterations of growth and metabolic factors characteristic of preeclampsia to imprint the immature gland with a lasting protective effect from later life breast tumorigenesis. If mechanistically substantiated, these findings could lead to a novel breast cancer prevention strategy. Citation Format: Powell M, Von Behren J, Neuhausen S, Reynolds P, Benz C. Functional IGF1R variant predicts preeclampsia protection from invasive breast cancer: Novel California teachers study findings [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-09-09.