Abstract P6-09-12: A functional single nucleotide polymorphisms in ABCC11, rs17822931, is associated with the risk of breast cancer in Japanese
Authors: Ishiguro J , Ito H , Tsukamo M , Iwata H , Nakagawa H , Matsuo K 
Published: February 2018

Background: ATP binding cassette (ABC) transporters are members of membrane protein of transporters, genetic variations of which may influence their activity. ABCC11, a member of ABC transporters, has been known to export steroid sulfates such as E2-17bG and E3S that are precursor of active estradiol. Therefore, rs17822931, a functional single nucleotide polymorphisms (SNP) in the ABCC11, may play a role in carcinogenesis of breast cancer (BC) via estrogen exposure. Three previous studies about the association of this polymorphism with BC risk reported inconsistent results. In this study, we aimed to evaluate the association between ABCC11 rs17822931 and BC risk in a Japanese population.

Subjects and Methods: We conducted a case-control study in 697 BC patients and 1394 age- and menopausal status- matched controls within the framework of the Hospital-based Epidemiological Research Program at Aichi Cancer Center II (HERPACC II). The odds ratio (OR) and 95 % confidence interval (CI) were calculated using the conditional logistic model adjusted for potential confounders to evaluate the association. We evaluated heterogeneity by BC subtype using Cochran's Q test, and that by estrogen exposure by multiplicative assumption in the conditional logistic regression model, which included an interaction term for genotype and estrogen exposure variable.

Results: Compared with A-allele, G allele was inversely associated with BC risk (a per allele OR=0.76, 95% CI, 0.61–0.94, P = 0.012). In the stratified analysis, we found that this association was observed only in estrogen receptor (ER) positive BC. A per-allele OR for ER positive BC was 0.65 (95% CI 0.49–0.86) while that for ER negative BC was 1.10 (95% CI 0.77-1.72). We found a statistically significant heterogeneity by ER status (p for interaction = 0.047). We did not observe any heterogeneity in the stratified analysis by other tumor characteristics. When stratifying by factors related with estrogen exposure, we found that this polymorphism had a different impact on BC risk by levels of exposure. Compared to women with low exposure to estrogen, those with high exposure had a stronger impact of this polymorphism. Per allele ORs for women who had ever and never breastfeeding were 0.82 (95% CI, 0.65-1.04) and 0.45 (0.26-0.79), respectively. We found suggestive heterogeneity between rs17822931 and history of breastfeeding on BC risk (p for interaction = 0.093). Interestingly, we found heterogeneous impact of rs17822931 by the levels of soy food consumption which is well known that may exert their effects as estrogen antagonists (p=0.005). We observed that ORs for &gt;50, 30-49 and &lt;30g/day of soy intake were 0.98 (0.65-1.46), 0.82 (0.59-1.14) and 0.45 (0.29-0.69), respectively.

Conclusion: Current case-control study showed the significant association between rs17822931 and the risk of BC, especially ER-positive BC, in Japanese women. Compared to women with low estrogen efflux activity with A allele, those with high efflux activity with G allele may have a lower risk of BC, especially in women with high estrogen exposure. To the best of our knowledge, this is the first study reporting the association between rs17822931 on ABCC11 and risk of BC considering levels of estrogen exposure.

Citation Format: Ishiguro J, Ito H, Tsukamo M, Iwata H, Nakagawa H, Matsuo K. A functional single nucleotide polymorphisms in ABCC11, rs17822931, is associated with the risk of breast cancer in Japanese [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-09-12.