Androgen receptor expression in normal breast tissue and subsequent breast cancer risk

Kevin H Kensler,Rulla M Tamimi,Bernard A Rosner,Yujing J Heng,Stuart J Schnitt,Aditi Hazra,Gabrielle M Baker,Francisco Beca,Myles Brown,Andrew H Beck,A Heather Eliassen,Susan E Hankinson

doi:10.1038/s41523-018-0085-3

Abstract

Sex steroid hormone signaling is critical in the development of breast cancers, although the role of the androgen receptor remains unclear. This study evaluated androgen receptor (AR) expression in normal breast tissue as a potential marker of breast cancer risk. We conducted a nested case–control study of women with benign breast disease (BBD) within the Nurses’ Health Studies. Epithelial AR expression was assessed by immunohistochemistry in normal tissue from the BBD biopsy and the percent of positive nuclei was estimated in ordinal categories of 10% for 78 breast cancer cases and 276 controls. Logistic regression models adjusting for the matching factors and BBD lesion type were used to calculate odds ratios (ORs) for the association between AR expression (tertiles: ≤10%, 11–30%, and >30%) and breast cancer risk. AR expression in normal breast tissue was not associated with subsequent breast cancer risk (ORT3vsT1 = 0.9, 95% CI = 0.4–1.8, p trend = 0.68). In comparison with low AR/low ER women, ORs of 0.4 (95% CI = 0.1–1.2) for high AR/high ER women, 1.8 (95% CI = 0.4–7.8) for low AR/high ER women, and 0.7 (95% CI = 0.3–1.6) for high AR/low ER women were observed (p interaction = 0.21). Ki67 did not modify the association between AR expression and breast cancer risk (p interaction = 0.75). There was little evidence for an overall association between AR expression in normal breast tissue and breast cancer risk. These findings did not show that the AR association varied by Ki67 expression in normal breast tissue, though there was suggestive heterogeneity by ER expression.

Highlights

Sex steroid hormones play a critical role in the development and progression of breast cancers.[1,2] While estrogen signaling has long been hypothesized to be a promoter of breast carcinogenesis,[3,4] the effects of androgen signaling are unclear
We evaluated androgen receptor (AR) expression in normal breast tissue as a potential predictor of subsequent breast cancer risk in a nested case–control study within the Nurses’ Health Study and Nurses’ Health Study II cohorts and whether this association differed by ER co-expression
The time elapsed between benign breast disease (BBD) biopsy and the index date was suggestively longer for controls

Summary

Introduction

Sex steroid hormones play a critical role in the development and progression of breast cancers.[1,2] While estrogen signaling has long been hypothesized to be a promoter of breast carcinogenesis,[3,4] the effects of androgen signaling are unclear. Circulating androgens are associated with breast cancer risk among postmenopausal women, conferring roughly twofold higher risk comparing highest-to-lowest quintiles.[5] Some of this apparent association may be due to the conversion of androgens to estrogens, leading to activation of estrogen signaling pathways in the breast. When circulating androgens are adjusted for circulating estradiol, these associations attenuate, but not entirely to unity, suggesting a potential effect of androgens on the breast, independent of their conversion to estrogens.[5,6,7] Circulating hormones show moderate correlations with hormone levels in the breast, indicating that these may be indirect markers of the hormonal milieu in the breast.[8,9,10,11,12]

Methods

Results

Conclusion