Role of Androgens on MCF-7 Breast Cancer Cell Growth and on the Inhibitory Effect of Letrozole

Abstract

Previous work has shown that androgens inhibit breast cancer cells and tumor growth. On the other hand, androgens can be converted to mitogenic estrogens by aromatase in breast cancer cells. Here, we report that androgens, such as the aromatizable androstenedione and the non-aromatizable 5A-dihydrotestosterone, inhibit MCF-7 cell proliferation. This effect is observed only in the absence or at a low concentration of estrogens and is evident in cells with low aromatase activity. Growth of a new aromatase stably transfected MCF-7 cell line (Ac1) was stimulated by conversion of androstenedione into estrogens and was sensitive to aromatase inhibitors. We show that blockade of the androgen receptor (AR) in these cells by the antiandrogen casodex or by the anti-AR small interfering RNA inhibited the antiproliferative effect of dihydrotestosterone and letrozole (aromatase inhibitor). We also show that suppression of the estrogen-induced antiapoptotic protein Bcl-2 may be involved in the antiproliferative effects of androgens and letrozole. These effects can be reversed by casodex. In conclusion, the results suggest that aromatase inhibitors may exert their antiproliferative effect not only by reducing the intracellular production of estrogens but also by unmasking the inhibitory effect of androgens acting via the AR. (Cancer Res 2006; 66(15): 7775-82)

The androgen metabolite 5α-androstane-3β,17β-diol (3βAdiol) induces breast cancer growth via estrogen receptor: implications for aromatase inhibitor resistance

“…A considerable amount of work has been done over the years studying the effects of androgens on the proliferation of breast cancer cells [1,[7][8][9][10][11][12]. The literature is, however, somewhat confusing, with conflicting data coming from relatively similar experimental systems.…”

“…Anti-androgens demonstrated mixed ability to inhibit the effects of DHT on growth, and this was attributed to the potential activity of un-indentified DHT metabolites [7]. Macedo et al later showed that DHT is growth-inhibitory in MCF-7 cells under low-estrogen conditions, and that this effect was mediated by the androgen receptor [1]. One common thread of much of this work is that many of the studies use culture systems in which it is possible that low, but significant, amounts of residual estrogen remain, and so may not adequately model the conditions present in a woman on AI therapy.…”

“…While the contributions of estrogens to breast cancer etiology are well established, the role of androgens in breast cancer development and progression is less well understood. Current dogma holds that androgens can inhibit the growth of breast cancer cells and that this effect is mediated through the androgen receptor [1].…”

“…We were therefore interested in the possibility that androgens and/or their downstream metabolites might play a role in resistance to AI therapy. A number of studies of the effects of androgens on breast cancer cells have been published, with the majority focusing on the effects of testosterone (TS) and 5α-dihydrotestosterone (DHT) on breast cancer growth [1,[7][8][9][10][11][12]. Little is known, however, about the effects of these compounds on breast cancer cell growth under conditions of profound estrogen deprivation, similar to conditions found in women treated with AIs.…”

New experimental models for aromatase inhibitor resistance

“…In terms of a suitable cell line that can be used for resistance studies, an ER-positive breast cancer line that does express high levels of aromatase is needed, but does not exist. MCF-7aro cells (stably transfected with the aromatase gene [38]) were generated in our lab and are used as a model system to study AI response and were therefore used to produce the drug resistant lines.…”