The cellular and molecular effects of the androgen receptor agonist, Cl-4AS-1, on breast cancer cells

ABSTRACT

Purpose: The androgen receptor (AR) has attracted attention in the treatment of breast cancer. Due to the undesirable side effects of AR agonists, attempts have been undertaken to develop selective AR modulators. One of these compounds is Cl-4AS-1. This study examined this compound more closely at the cellular and molecular levels. Methods: Three different breast cancer cell lines were utilized, namely the luminal MCF-7 cells, the molecular apocrine MDA-MB-453 cells, and the triple negative, basal MDA-MB-231 cells. Results: High and significant concordance between dihydrotestosterone (DHT) and Cl-4AS-1 in regulation of gene expression in MDA-MB-453 cells was found. However, some differences were noted including the expression of AR, which was upregulated by DHT, but not Cl-4AS-1. In addition, both DHT and Cl-4AS-1 caused a similar morphological change and reorganization of the actin structure of MDA-MB-453 cells into a mesenchymal phenotype. Treatment of cells with DHT resulted in induction of proliferation of MCF-7 and MDA-MB-453 cells, but no effect was observed on the growth of MDA-MB-231 cells. On the other hand, increasing doses of Cl-4AS-1 resulted in a dose-dependent inhibition on the growth of the three cell lines. This inhibition was a result of induction of apoptosis whereby Cl-4AS-1 caused a block in entry of cells into the S-phase followed by DNA degradation. Conclusions: These results indicate that although Cl-4AS-1 has characteristics of classical AR agonist, it has dissimilar properties that may make it useful in treating breast cancer.

KEYWORDS:

• Apoptosis
• Cl-4AS-1
• gene expression
• morphology
• SARM

Supplemental data

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Acknowledgments

The authors would like to extend their gratitude to Dr Adeeb Zoubi and Ms Mahasen Zalloum of Stem Cells Arabia for their assistance in the flow cytometry. We would also like to thank Prof. Mohammad El-Khateeb, Ms Khadijah Al-Rashed, Ms Razan Abu Khashabeh, and Ms Ala’a Arafat at the National Center for Diabetes, Endocrinology and Genetics for their technical assistance.

Declaration of interest

The authors report no conflict of interest. The authors alone are responsible for the content and writing of the paper.

Additional information

Funding

This work has been funded by the Deanship of Scientific Research, The University of Jordan grant number [1436/2012] and by the Scientific Research Support Fund, Ministry of Higher Education and Scientific Research grant number [MPH/1/06/2012].