The potential clinical benefit of targeting androgen receptor (AR) in estrogen-receptor positive breast cancer cells treated with Exemestane

https://doi.org/10.1016/j.bbadis.2019.165661Get rights and content
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Highlights

  • Exemestane induces androgen receptor (AR) overexpression/activation in breast cancer cells.

  • Targeting AR in Exemestane-sensitive cells enhances breast cancer cell death.

  • Targeting AR re-sensitizes Exemestane-resistant breast cancer cells.

  • Exemestane-resistant breast cancer cells have an AR-dependent but ER-independent mechanism.

  • AR antagonism is an attractive therapeutic strategy to improve breast cancer treatment with Exemestane.

Abstract

The development of acquired resistance to the aromatase inhibitors (AIs) used in clinic is being considered the major concern in estrogen-receptor positive (ER+) breast cancer therapy. Recently, androgen receptor (AR) has gained attention in the clinical setting, since it has been implicated in AIs-resistance, although, different roles for AR in cell fate have been described. In this work, our group elucidates, for the first time, the oncogenic role of AR in sensitive and resistant ER+ breast cancer cells treated with the potent third-generation steroidal AI Exemestane (Exe). We demonstrate that Exe promotes an overexpression/activation of AR, which has an oncogenic and pro-survival role in Exe-sensitive and Exe-resistant cells. Moreover, we also disclose that targeting AR with bicalutamide (CDX) in Exe-treated cells, enhances the efficacy of this AI in sensitive cells and re-sensitizes resistant cells to Exe treatment. Furthermore, by targeting AR in Exe-resistant cells, it is also possible to block the activation of the ERK1/2 and PI3K cell survival pathways, hamper ERα activation and increase ERβ expression. Thus, this study, highlights a new mechanism involved in Exe-acquired resistance, implicating AR as a key molecule in this setting and suggesting that Exe-resistant cells may have an AR-dependent but ER-independent mechanism. Hence we propose AR antagonism as a potential and attractive therapeutic strategy to overcome Exe-acquired resistance or to enhance the growth inhibitory properties of Exe on ER+ breast cancer cells, improving breast cancer treatment.

Keywords

Breast cancer
Acquired resistance
Aromatase Inhibitors
Exemestane
Androgen receptor
Bicalutamide

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