AR collaborates with ERα in aromatase inhibitor-resistant breast cancer.

Abstract

Androgen receptor (AR) is an attractive target in breast cancer because of its frequent expression in all the molecular subtypes, especially in estrogen receptor (ER)-positive luminal breast cancers. We have previously shown a role for AR overexpression in tamoxifen resistance. We engineered ER-positive MCF-7 cells to overexpress aromatase and AR (MCF-7 AR Arom cells) to explore the role of AR in aromatase inhibitor (AI) resistance. Androstendione (AD) was used as a substrate for aromatization to estrogen. The nonsteroidal AI anastrazole (Ana) inhibited AD-stimulated growth and ER transcriptional activity in MCF-7 Arom cells, but not in MCF-7 AR Arom cells. Enhanced activation of pIGF-1R and pAKT was found in AR-overexpressing cells, and their inhibitors restored sensitivity to Ana, suggesting that these pathways represent escape survival mechanisms. Sensitivity to Ana was restored with AR antagonists, or the antiestrogen fulvestrant. These results suggest that both AR and ERα must be blocked to restore sensitivity to hormonal therapies in AR-overexpressing ERα-positive breast cancers. AR contributed to ERα transcriptional activity in MCF-7 AR Arom cells, and AR and ERα co-localized in AD + Ana-treated cells, suggesting cooperation between the two receptors. AR-mediated resistance was associated with a failure to block ER transcriptional activity and enhanced up-regulation of AR and ER-responsive gene expression. Clinically, it may be necessary to block both AR and ERα in patients whose tumors express elevated levels of AR. In addition, inhibitors to the AKT/IGF-1R signaling pathways may provide alternative approaches to block escape pathways and restore hormone sensitivity in resistant breast tumors.

• Authors: Yassine Rechoum, Daniela Rovito, Domenico Iacopetta, Ines Barone, Sebastiano Andò, Nancy L Weigel, Bert W O'Malley, Powel H Brown, Suzanne A W Fuqua
• Journal: Breast cancer research and treatment (Breast Cancer Res Treat) Vol. 147 Issue 3 Pg. 473-85 (Oct 2014) ISSN: 1573-7217 [Electronic] Netherlands
• PMID: 25178514 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• AR protein, human
• Aromatase Inhibitors
• ESR1 protein, human
• Estrogen Receptor Antagonists
• Estrogen Receptor alpha
• Nitriles
• Receptors, Androgen
• Triazoles
• Tamoxifen
• Fulvestrant
• Anastrozole
• Androstenedione
• Estradiol
• Receptor, IGF Type 1
• Proto-Oncogene Proteins c-akt

Topics

• Anastrozole
• Androstenedione (pharmacology)
• Aromatase Inhibitors (pharmacology)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Drug Resistance, Neoplasm (drug effects)
• Estradiol (analogs & derivatives, pharmacology)
• Estrogen Receptor Antagonists (pharmacology)
• Estrogen Receptor alpha (metabolism)
• Female
• Fulvestrant
• Humans
• MCF-7 Cells (drug effects)
• Nitriles (pharmacology)
• Phosphorylation
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptor, IGF Type 1 (metabolism)
• Receptors, Androgen (genetics, metabolism)
• Tamoxifen (pharmacology)
• Triazoles (pharmacology)