Abstract
BackgroundAndrogens, through their own receptor, play a protective role on breast tumor development and progression and counterbalance estrogen-dependent growth stimuli which are intimately linked to breast carcinogenesis.MethodsCell counting by trypan blu exclusion was used to study androgen effect on estrogen-dependent breast tumor growth. Quantitative Real Time RT–PCR, western blotting, transient transfection, protein immunoprecipitation and chromatin immunoprecipitation assays were carried out to investigate how androgen treatment and/or androgen receptor overexpression influences the functional interaction between the steroid receptor coactivator AIB1 and the estrogen- or androgen receptor which, in turn affects the estrogen-induced cyclin D1 gene expression in MCF-7 breast cancer cells. Data were analyzed by ANOVA.ResultsHere we demonstrated, in estrogen receptor α (ERα)-positive breast cancer cells, an androgen-dependent mechanism through which ligand-activated androgen receptor (AR) decreases estradiol-induced cyclin D1 protein, mRNA and gene promoter activity. These effects involve the competition between AR and ERα for the interaction with the steroid receptor coactivator AIB1, a limiting factor in the functional coupling of the ERα with the cyclin D1 promoter. Indeed, AIB1 overexpression is able to reverse the down-regulatory effects exerted by AR on ERα-mediated induction of cyclin D1 promoter activity. Co-immunoprecipitation studies indicated that the preferential interaction of AIB1 with ERα or AR depends on the intracellular expression levels of the two steroid receptors. In addition, ChIP analysis evidenced that androgen administration decreased E2-induced recruitment of AIB1 on the AP-1 site containing region of the cyclin D1 gene promoter.ConclusionsTaken together all these data support the hypothesis that AIB1 sequestration by AR may be an effective mechanism to explain the reduction of estrogen-induced cyclin D1 gene activity. In estrogen-dependent breast cancer cell proliferation, these findings reinforce the possibility that targeting AR signalling may potentiate the effectiveness of anti-estrogen adjuvant therapies.
Highlights
Androgens, through their own receptor, play a protective role on breast tumor development and progression and counterbalance estrogen-dependent growth stimuli which are intimately linked to breast carcinogenesis
We propose that the competition for the steroid receptor coactivator Amplified in Breast Cancer 1 (AIB1), that is important in the functional coupling of the estrogen receptor α (ERα) with the cyclin D1 promoter [28], may represent a possible mechanism through which androgen receptor (AR) can modulate ERα-mediated signalling pathway on cyclin D1 gene leading to the inhibition of breast cancer cell proliferation
Inhibition of estrogen-dependent proliferation by androgen receptor over-expression We previously demonstrated that MCF-7 cells are androgen-responsive and that DHT treatment induces a transient increase in AR protein levels [22] similar to that seen in other cell types [31, 32]
Summary
Through their own receptor, play a protective role on breast tumor development and progression and counterbalance estrogen-dependent growth stimuli which are intimately linked to breast carcinogenesis. AR signalling influence on breast cancer depends on the contest of the different subtype of disease [3] as indicated by a number of studies showing that the expression of AR is a favourable determinant of survival in estrogen receptor alpha (ERα)-positive, but not ERα-negative breast cancer patients [7,8,9]. A wide study, conducted on 4147 pre- and postmenopausal women with invasive breast cancer found that, in the 7 years following diagnosis, AR expression was associated with improved prognosis in ERα-positive tumors and worse prognosis in ERαnegative ones [10]
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