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The Potential Clinical Benefit of Targeting Androgen Receptor (AR) in Estrogen-Receptor Positive Breast Cancer Cells Treated With Exemestane

The Potential Clinical Benefit of Targeting Androgen Receptor (AR) in Estrogen-Receptor Positive Breast Cancer Cells Treated With Exemestane

Cristina Amaral, Tiago V Augusto, Marta Almada, Sara C Cunha, Georgina Correia-da-Silva, Natércia Teixeira

Biochim Biophys Acta Mol Basis Dis. 2020 May 1;1866(5):165661.

PMID: 31891807

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP90357065-A	Bicalutamide (CDX)		90357-06-5	Price

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