Preclinical evaluation of the AR inhibitor enzalutamide in triple-negative breast cancer cells

Abstract

The androgen receptor (AR) is present in approximately 80% of invasive breast cancer patients and in up to 30% of patients with triple-negative breast cancer (TNBC). Therefore, our aim was to investigate the targeting of AR as a possible hormonal approach to the treatment of TNBC. Analysis of 2091 patients revealed an association between AR expression and poor overall survival, selectively in patients with the basal subtype of breast cancer, the vast majority of which are TNBC. IC 50 values for the secondgeneration anti-androgen enzalutamide across 11 breast cancer cell lines varied from 4 µM to >50 µM. The activity of enzalutamide was similar in TN and non-TN cell lines but was dependent on the presence of AR. Enzalutamide reduced clonogenic potential and cell growth in a 3D matrix in AR-positive cells. In addition, enzalutamide also inhibited cell migration and invasion in an AR-dependent manner. Enzalutamide appeared to mediate these processes through down-regulation of the transcription factors AP-1 and SP-1. The first-generation anti-androgen flutamide similarly blocked cell growth, migration and invasion. AR-positive TNBC cells clustered separately from AR-negative cells based on an androgen-related gene expression signature, independently of TNBC subtype. We conclude that targeting of the AR with drugs such as enzalutamide may provide an alternative treatment strategy for patients with AR-positive TNBC.

Androgen Receptor Expression and Bicalutamide Antagonize Androgen Receptor Inhibit β-Catenin Transcription Complex in Estrogen Receptor-Negative Breast Cancer

“…This regulatory network indicates a reciprocal link between AR and Wnt/β-catenin pathways in ER-negative breast cancer. Although the existence of AR in breast cancer has been studied for decades, it has not been widely investigated as a potential therapeutic target in malignant breast neoplasms [28]. …”

Prognostic Significance of Androgen Receptor Expression in Triple Negative Breast Cancer: A Systematic Review and Meta-Analysis

“…Enzalutamide is a potent AR inhibitor that acts on multiple targets in the AR signaling pathway. 64 Data from published studies indicated that a subset of patients with AR-positive TNBC may benefit from AR targeting agents. [65][66][67] These findings should be validated through additional research and meta-analyses.…”

“…Currently, the median survival time of patients with mTNBC is about 1 year from metastatic diagnosis. 68 Evidence from recent studies 64 demonstrates that antiandrogen therapy suppresses the growth, invasion, and migration of AR-positive TNBC cell lines. To increase homogeneity among the included studies, studies reporting on metastatic disease and anti-androgen therapy were excluded.…”

The Missing Lnc: The Potential of Targeting Triple-Negative Breast Cancer and Cancer Stem Cells by Inhibiting Long Non-Coding RNAs

“…Novel targeted therapies based on the unique molecular characteristics and mutations associated with TNBCs are being tested, including inhibitors for poly-ADP ribose polymerase (PARP) [29], phosphoinositide 3-kinase (PI3K) [30], mitogen-activated protein kinase (MEK) [31][32][33][34], heat shock protein-90 (Hsp90) [35], histone deacetylases [36], and androgens [37]. Moreover, some evidence suggests immunotherapies may work on TNBCs [38].…”