Alterations associated with androgen receptor gene activation in salivary duct carcinoma of both sexes: Potential therapeutic ramifications

Yoshitsugu Mitani, Pulivarthi H. Rao, Sankar N. Maity, Yu Chen Lee, Renata Ferrarotto, Julian C. Post, Lisa Licitra, Scott M. Lippman, Merrill S. Kies, Randal S. Weber, Carlos Caulin, Sue Hwa Lin, Adel K. El-Naggar

Research output: Contribution to journalArticle

Abstract

Purpose: To investigate the molecular events associated with the activation of androgen receptor (AR) as a potential therapeutic target in patients with salivary duct carcinoma (SDC).

Experimental Design: Comprehensive molecular and expression analysis of the AR gene in 35 tumor specimens (20 males and 15 females) and cell lines derived from SDC using Western blotting and RT-PCR, FISH analysis, and DNA sequencing was conducted. In vitro and in vivo animal studies were also performed.

Results: AR expression was detected in 70% of the tumors and was mainly nuclear and homogenous in both male and female SDCs, although variable cytoplasmic and/or nuclear localization was also found. We report the identification of ligand-independent AR splice variants, mutations, and extra AR gene copy in primary untreated SDC tumors. In contrast to prostate cancer, no AR gene amplification was observed. In vitro knockdown of AR in a female derived SDC cell line revealed marked growth inhibition in culture and in vivo androgen-independent tumor growth.

Conclusions: Our study provides new detailed information on the molecular and structural alterations associated with AR gene activation in SDC and sheds more light on the putative functional role of AR in SDC cells. On the basis of these data, we propose that patients with SDC (male and female) can be stratified for hormone-based therapy in future clinical trials.

Original languageEnglish
Pages (from-to)6570-6581
Number of pages12
JournalClinical Cancer Research
Volume20
Issue number24
DOIs
Publication statusPublished - Dec 15 2014

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Mitani, Y., Rao, P. H., Maity, S. N., Lee, Y. C., Ferrarotto, R., Post, J. C., Licitra, L., Lippman, S. M., Kies, M. S., Weber, R. S., Caulin, C., Lin, S. H., & El-Naggar, A. K. (2014). Alterations associated with androgen receptor gene activation in salivary duct carcinoma of both sexes: Potential therapeutic ramifications. Clinical Cancer Research, 20(24), 6570-6581. https://doi.org/10.1158/1078-0432.CCR-14-1746