Androgens and the breast

Abstract

Androgens have important physiological effects in women while at the same time they may be implicated in breast cancer pathologies. However, data on the effects of androgens on mammary epithelial proliferation and/or breast cancer incidence are not in full agreement. We performed a literature review evaluating current clinical, genetic and epidemiological data regarding the role of androgens in mammary growth and neoplasia. Epidemiological studies appear to have significant methodological limitations and thus provide inconclusive results. The study of molecular defects involving androgenic pathways in breast cancer is still in its infancy. Clinical and nonhuman primate studies suggest that androgens inhibit mammary epithelial proliferation and breast growth while conventional estrogen treatment suppresses endogenous androgens. Abundant clinical evidence suggests that androgens normally inhibit mammary epithelial proliferation and breast growth. Suppression of androgens using conventional estrogen treatment may thus enhance estrogenic breast stimulation and possibly breast cancer risk. Addition of testosterone to the usual hormone therapy regimen may diminish the estrogen/progestin increase in breast cancer risk but the impact of this combined use on mammary gland homeostasis still needs evaluation.

Figure 1

Schematic design of the androgen receptor gene (top) and protein (below). The polymorphic trinucleotide repeat site (CAG) is indicated in green at the left. Trans-activating function (TAF), DNA-binding (DBD) and ligand-binding domains (LBD) are labeled.

Figure 2

Average estradiol (E2) and testosterone (T) levels across the female lifespan. Y-axis, level in picograms; X-axis, age in years. Dashed lines predict changes in T and E2 hormone levels resulting from estrogen replacement therapy (ERT) beginning at menopause.

Figure 3

Mammary epithelial proliferation shown by Ki67 immunoreactivity (brown dots) in ovariectomized monkeys treated with (a) placebo (Con), (b) estradiol (E2), (c) E2 and progesterone (P4), (d) tamoxifen (Tam) and (e) E2 and testosterone (T). (f) Quantification of the Ki67 proliferation index. Proliferation is increased with E2 or E2 and P4 (E/P), while this increase is attenuated by the addition of T to E2 (E/T). All differences are statistically significant when compared to the placebo group. Data from Zhou and colleagues [53].