Androgen Receptor Signaling in Salivary Gland Cancer

Abstract

Salivary gland cancers comprise a small subset of human malignancies, and are classified into multiple subtypes that exhibit diverse histology, molecular biology and clinical presentation. Local disease is potentially curable with surgery, which may be combined with adjuvant radiotherapy. However, metastatic or unresectable tumors rarely respond to chemotherapy and carry a poorer prognosis. Recent molecular studies have shown evidence of androgen receptor signaling in several types of salivary gland cancer, mainly salivary duct carcinoma. Successful treatment with anti-androgen therapy in other androgen receptor-positive malignancies such as prostate and breast cancer has inspired researchers to investigate this treatment in salivary gland cancer as well. In this review, we describe the prevalence, biology, and therapeutic implications of androgen receptor signaling in salivary gland cancer.

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

“…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].…”

“…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]. Presence of AR-V7 in circulating tumor cells has been associated with resistance to androgen deprivation therapy in prostate cancers [54], but it is unclear whether presence of AR-V7 in tumor tissue in SDC would be associated with outcome or therapeutic resistance.…”

“…Some SDC tumors also have mutations in FOXA1 , which may impair androgen receptor signaling and has been linked to resistance to androgen deprivation therapy in prostate cancer [49]. The role of androgen receptor signaling in salivary gland cancers has been extensively reviewed elsewhere [53]. …”

“…Preclinical studies of SDC cell lines have shown that androgens can enhance cell growth, and proliferation of SDC cells is mitigated by inhibition or knockdown of androgen receptors [52, 79]. Similar to trastuzumab, several single-case reports, summarized in prior reviews [13, 53], have shown complete and/or prolonged responses in patients with recurrent/metastatic SDC treated with androgen receptor inhibitors such as bicalutamide or enzalutamide. AR inhibitors are often used in combination with GnRH/LHRH agonists (triptorelin or goserelin), which inhibit the production of androgens (Figure 2).…”

“…Percentages for each alteration were obtained by totaling the number of positive cases (by IHC or sequencing for ErbB2, EGFR, AR) divided by total cases found in the literature [3, 4, 6, 7, 15, 18, 22, 28, 33, 39, 40, 44, 49–53, 55, 57–64, 67, 86–91]. Percentages representing expression are best estimates, as positivity was defined heterogeneously among studies.…”