Androgen receptor overexpression induces tamoxifen resistance in human breast cancer cells

Abstract

Although the androgen receptor (AR) is a known clinical target in prostate cancer, little is known about its possible role in breast cancer. We have investigated the role of AR expression in human breast cancer in response to treatment with the antiestrogen tamoxifen. Resistance to tamoxifen is a major problem in treating women with breast cancer. By gene expression profiling, we found elevated AR, and reduced estrogen receptor (ER) α mRNA in tamoxifen-resistant tumors. Exogenous overexpression of AR rendered ERα-positive MCF-7 breast cancer cells resistant to the growth-inhibitory effects of tamoxifen in anchorage-independent growth assays, and in xenograft studies in athymic nude mice. AR-overexpressing cells remained sensitive to growth stimulation with dihydrotestosterone. Treatment with the AR antagonist Casodex ™ (bicalutamide) reversed this resistance, demonstrating the involvement of AR signaling in tamoxifen resistance. In AR-overexpressing cells, tamoxifen induced transcriptional activation by ERα that could be blocked by Casodex, suggesting that AR overexpression enhances tamoxifen's agonistic properties. Our data suggest a role for AR overexpression as a novel mechanism of hormone resistance, so that AR may offer a new clinical therapeutic target in human breast cancers.

Androgen receptor expression is a significant prognostic factor in estrogen receptor positive breast cancers

“…Although a statistically significant interaction between chemotherapy and the expression of AR was not demonstrated, our results confirmed both by uni-and multivariate analysis a significant correlation of AR positive immunoreaction and longer DSS in patients treated with any chemotherapeutic regimen containing CMF and also with regimens containing an anthracycline, while there was not a significant correlation of AR with survival in patients treated with taxanes or vinorelbine. On the other hand, recent experimental data suggest a role for AR overexpression as a novel mechanism of tamoxifen resistance and speculate that AR and ER could collaborate to regulate cyclin D1 gene expression, thereby promoting cell cycle progression in the presence of tamoxifen [25]. Taken together these data may suggest that AR/ER positive breast cancer with high Ki67 expression could resist to tamoxifen therapy and benefit from specific chemotherapeutic treatment containing CMF and/or anthracyclines.…”

Androgen receptor expression in male breast cancer predicts inferior outcome and poor response to tamoxifen treatment

“…In addition, for the first time, we studied the relationship between AR status and tamoxifen response in metastatic MBC patients and found that AR-positive patients have a poor clinical benefit rate than AR-negative patients. Certain reports have shown that AR over-expression induces tamoxifen resistance in human breast cancer, and they speculate that AR and ERa could collaborate to regulate cyclin D1 gene expression and promote cell cycle progression in tamoxifen-resistant cells (27). It has been demonstrated that the AR amino-terminal domain and ERa ligand-binding domain can interfere with each other via oestrogen (28).…”

Androgen receptor signaling pathways as a target for breast cancer treatment

“…Preclinical data have shown that AR overexpression may induce tamoxifen resistance (Peters et al 2009) and that antagonism of AR may restore tamoxifen sensitivity by inhibiting the ER agonist response of tamoxifen (De Amicis et al 2010). In patients with ER-positive BCs, a high AR:ER (≥2.0) ratio has been shown to be associated with a greater than four-fold increased risk of failure while on tamoxifen (HR = 0.43) and is also an independent predictor of diseasefree and disease-specific survival (Cochrane et al 2014).…”