Abstract 4295: Androgen receptor expression in normal breast TDLUs and subsequent breast cancer risk

Abstract

Abstract Background Sex steroid hormone signaling is critical in the development and progression of breast cancers, though the role of androgens remains unspecified. Large epidemiologic studies have found a consistent association between circulating androgens and increased breast cancer risk, though it is unknown whether circulating androgens reflect the androgenic milieu in the breast. An interaction between androgen receptor (AR) and estrogen receptor (ER) signaling in the breast has been postulated, wherein AR signaling antagonizes ER signaling in estrogen-rich environments, and AR signaling induces proliferative effects in estrogen-deplete environments. Methods We evaluated the association between AR expression and subsequent breast cancer risk in a nested case-control study of women with benign breast disease (BBD) within the Nurses’ Health Studies. Cases were women with BBD that subsequently developed breast cancer (median 9 years later) while controls had BBD but did not develop breast cancer. Tissue microarrays were constructed containing normal terminal ductal lobular unit (TDLU) tissue from the BBD biopsy. AR expression was assessed by immunohistochemistry and the percent of positive-staining nuclei was digitally quantified for 61 breast cancer cases and 184 controls. Logistic regression models adjusting for the year of BBD biopsy, age at cancer diagnosis, years since BBD biopsy, and BBD lesion type were used to calculate odds ratios and 95% confidence intervals for the association between the tertile of AR expression and breast cancer risk. We further evaluated the impact of AR and ER co-expression, each dichotomized at the median, in a sub-analysis of 31 cases and 82 controls. Finally, we assessed AR expression as a predictor of subsequent ER tumor status using polytomous logistic regression. Results Overall, women in the highest tertile of AR expression experienced non-significant 1.32-fold increased odds of breast cancer (95% CI: 0.64-1.73, p-trend = 0.559) compared to the lowest tertile. A significant interaction was detected between AR and ER co-expression in normal breast TDLUs and subsequent breast cancer risk (p-interaction = 0.003). Among women with low ER expression, increased AR expression was associated with 2.52-fold increased odds (95% CI: 0.68-9.34) of developing breast cancer. In contrast, among women with high ER expression, high AR expression was associated with a 91% decrease in the odds (OR = 0.09, 95% CI: 0.01-0.62) of breast cancer. AR expression was not predictive of subsequent ER tumor status. Conclusions There was little evidence for an overall association between AR expression in normal breast tissue and breast cancer risk, though we observed a significant interaction between AR and ER expression. Our findings support the hypothesis that AR interacts with ER to promote cell proliferation in estrogen-deprived environments and inhibit growth in estrogen-rich environments. Citation Format: Kevin Kensler, Andrew Beck, Francisco Beca, Laura Collins, Stuart Schnitt, Aditi Hazra, Susan Hankinson, Myles Brown, Rulla Tamimi. Androgen receptor expression in normal breast TDLUs and subsequent breast cancer risk. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4295.