Alterations Associated with Androgen Receptor Gene Activation in Salivary Duct Carcinoma of Both Sexes: Potential Therapeutic Ramifications

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 were 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 shed more light on the putative functional role of AR in SDC cells. Based on these data, we propose that patients with SDC (male and female) can be stratified for hormone-based therapy in future clinical trials.

Salivary duct carcinoma: An aggressive salivary gland malignancy with opportunities for targeted therapy

“…The authors concluded that AR-negative SDC must be extremely rare, and that some specimens diagnosed as SDC without AR positivity may be misclassified. Androgen receptor expression appears to be more common in SDCs from men than in SDCs from women [40, 52]. Studies investigating the prognostic significance of AR positivity have shown mixed results [6, 18, 33, 49, 52].…”

“…Androgen receptor expression appears to be more common in SDCs from men than in SDCs from women [40, 52]. Studies investigating the prognostic significance of AR positivity have shown mixed results [6, 18, 33, 49, 52]. Genetic alterations in androgen receptors noted in SDC specimens include mutations and extra gene copies, but not gene amplification as seen in prostate cancer [49, 52, 53].…”

“…Studies investigating the prognostic significance of AR positivity have shown mixed results [6, 18, 33, 49, 52]. Genetic alterations in androgen receptors noted in SDC specimens include mutations and extra gene copies, but not gene amplification as seen in prostate cancer [49, 52, 53]. Androgen receptor splice variants missing exons needed for receptor activation, in particular the AR-V7 splice variant, are expressed in a significant number of SDC specimens; these AR splice variants encode a truncated AR protein that has only the transactivating N-terminal domain without the C-terminal ligand binding domain, which results in constitutive activation of AR [52, 53].…”

Salivary Duct Carcinoma: An Update on Morphologic Mimics and Diagnostic Use of Androgen Receptor Immunohistochemistry

“…The retro-auricular tumor regressed in response to anti-testosterone therapy. Currently, ADT in patients with SDC is being actively studied [30] and several similarities and differences between AR pathway activation in SDC and prostate cancer have been delineated [31]. For instance, a subset of hormone therapy-naïve SDCs harbor oncogenic AR splice variants (including AR-V7), which have been associated with resistance to ADT in advanced prostate cancer.…”

“…In contrast, no activating AR mutations or AR gene amplifications have been identified in hormone therapy-naïve SDC. In the future, SDC patients may be selected for ADT clinical trials based on AR isoforms [31].…”