15P - Estrogen-dependent breast cancer: the importance of androgen receptor in exemestane treatment

Date 11 September 2017
Event ESMO 2017 Congress
Session Poster display session
Topics Basic Science
Breast Cancer
Presenter Cristina Amaral
Citation Annals of Oncology (2017) 28 (suppl_5): v1-v21. 10.1093/annonc/mdx361
Authors C. Amaral1, T. Augusto1, F. Roleira2, E. Tavares-Da-Silva2, G. Correia-Da-Silva1, N. Teixeira1
  • 1Laboratory Of Biochemistry, Department Of Biological Sciences, UCIBIO,REQUIMTE, Faculty of Pharmacy, University of Porto, 4050-313 - Porto/PT
  • 2Pharmaceutical Chemistry Group, Faculty of Pharmacy, University of Coimbra, 000-548 - Coimbra/PT

Abstract

Background

Exemestane (Exe) is a third-generation steroidal aromatase inhibitor (AI) that is a standard therapeutic approach for post-menopausal women with estrogen-receptor positive (ER+) breast cancer. Besides its clinical benefit, acquired resistance may develop. Thus, to avoid this drawback it is urgent to find new targets that can improve breast cancer treatment. It is known that 85-95% of the ER+ breast cancers, overexpress androgen receptor (AR), that has a dual function in breast cancer depending on hormonal cell status. It has been described that in AIs-sensitive breast cancer cells this receptor promotes cell death. Several clinical trials are ongoing to study the efficacy of combining AR antagonists, as bicalutamide (CDX), with Exe, but the benefit of targeting AR is not well defined. In that way, this work will investigate the biological significance of AR in Exe-treated breast cancer cells and the effectiveness of targeting AR.

Methods

In ER+ breast cancer cells that overexpress aromatase (MCF-7aro), it was investigated the in vitro effects of the AR antagonist CDX in Exe-treated cells. The cell impact in viability and cell proliferation was studied using MTT assay and flow cytometry, respectively. The cell death was explored by evaluating caspase activities. The expression/activation of AR and the effects on PI3K and MAPK pathways were studied by Western-blot.

Results

Exe induces an overexpression and hyperactivation of AR in MCF-7aro cells. By blocking AR with CDX, it was observed an increase in the reduction of viability and proliferation of Exe-treated cells, when comparing to Exe alone. An increase in activation of caspases-9, -8 and -7 was also observed for the combination. In addition, CDX inhibits the Exe-induced activation of cell proliferation/survival MAPK pathway and caused no effect on PI3K pathway.

Conclusions

This study suggests that, contrary what is described for other AIs, the AR as a pro-survival role in sensitive breast cancer cells treated with Exe and that by targeting AR it is possible to improve the clinical efficacy of Exe, by inhibiting cell proliferation and inducing apoptosis. This work contributes to the understanding of the link between AR and Exe and will highlight new targets to improve breast cancer treatment.

Clinical trial identification

Legal entity responsible for the study

UCIBIO, REQUIMTE, Faculty of Pharmacy, University of Porto

Funding

Fundação para a Ciência e a Tecnologia (FCT): Amaral C. (SFRH/BPD/98304/2013) and Augusto T. (BD/128333/2017) grants

Disclosure

All authors have declared no conflicts of interest.