AIB1 sequestration by androgen receptor inhibits estrogen-dependent cyclin D1 expression in breast cancer cells.

Abstract

BACKGROUND:

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.

METHODS:

Cell 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.

RESULTS:

Here 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.

CONCLUSIONS:

Taken 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.

• Authors: Francesca De Amicis, Chiara Chiodo, Catia Morelli, Ivan Casaburi, Stefania Marsico, Rosalinda Bruno, Diego Sisci, Sebastiano Andò, Marilena Lanzino
• Journal: BMC cancer (BMC Cancer) Vol. 19 Issue 1 Pg. 1038 (Nov 04 2019) ISSN: 1471-2407 [Electronic] England
• PMID: 31684907 (Publication Type: Journal Article)

Chemical References

• Estrogen Receptor alpha
• RNA, Messenger
• Receptors, Androgen
• Transcription Factor AP-1
• Cyclin D1
• Estradiol
• NCOA3 protein, human
• Nuclear Receptor Coactivator 3

Topics

• Breast Neoplasms (metabolism)
• Cyclin D1 (genetics, metabolism)
• Estradiol (metabolism)
• Estrogen Receptor alpha (metabolism)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• MCF-7 Cells
• Nuclear Receptor Coactivator 3 (genetics, metabolism)
• Promoter Regions, Genetic (genetics)
• Protein Binding
• RNA, Messenger (genetics)
• Receptors, Androgen (metabolism)
• Signal Transduction
• Transcription Factor AP-1 (genetics)