Nuclear loss and cytoplasmic expression of androgen receptor in penile carcinomas: role as a driver event and as a prognosis factor

Abstract

Androgen receptor (AR) is a member of the steroid and nuclear family receptor that acts as transcription factor. AR signaling plays pivotal role in the development and progression of prostate cancer. However, the role of AR in penile cancer (PeCa) is poorly explored. Our previous molecular studies unveiled frequent AR mRNA loss in PeCa, which was further predicted as a major driver alteration in this neoplasm. Herein, we assessed the AR protein expression in 59 usual PeCa tissues and 42 surrounding normal tissues (SNT) by immunohistochemistry using a tissue microarray. In a paired analysis, we found a total absence of nuclear AR expression in PeCa while 95.2% of SNT samples presented strong nuclear AR expression (P < 0.001). Interestingly, 17 of 42 PeCa presented weak or moderate cytoplasmic AR staining, contrasting with 5 of 42 SNT (P = 0.008). Increased levels of AR cytoplasmic expression were related with poor prognosis features including advanced clinical staging (P = 0.044), compromised surgical margins (P = 0.005), and pathological inguinal node status (P = 0.047). Furthermore, AR cytoplasmic expression was also related with shorter overall survival (P = 0.032). In conclusion, the frequent loss of nuclear AR protein levels suggests a potential function in PeCa development. Based on this result, the androgen deprivation therapy is not indicated for PeCa patients. In addition, the AR cytoplasmic expression found in a significant number of cases (40.5%) showed prognostic value and pathways activated by the non-genomic AR signaling may represent a promising therapeutic strategy.

P-Glycoprotein and Androgen Receptor Expression Reveals Independence of Canine Prostate Cancer from Androgen Hormone Stimulation

“…Non-nuclear AR expression was recently reported in canine PC [19,44]. However, in human cancers, including PC, non-nuclear AR signaling has been associated with aggressive characteristics, including epithelial-mesenchymal transition and metastasis [45,46]. AR nuclear expression is associated with hormone-dependent signaling pathways; however, AR splice variants can be found with different cellular localization, with a clinical impact on human patients [47].…”

Penile Cancer-Derived Cells Molecularly Characterized as Models to Guide Targeted Therapies

“…Several potentially targetable dysregulated oncogenic pathways have been described in PeCa [9,38,[72][73][74], including PI3K/Akt/mTOR, EGFR, and ERRB2, among others. Recently, clinical trials testing immunotherapy in PeCa patients have shown promising results [75].…”

Molecular and Functional Links between Neurodevelopmental Processes and Treatment-Induced Neuroendocrine Plasticity in Prostate Cancer Progression

“…Interestingly, in addition to canonical AR signaling in the nucleus, nongenomic AR signaling occurs in the cytoplasm [119]. In penile carcinomas, non-genomic AR signaling has been suggested to play a role and to correlate with poor prognosis and relate to shorter overall survival [120]. It is unknown whether the cytoplasmic AR attracts signals from the surrounding stromal cells or sympathetic nerves located in the prostate cancer tumor microenvironment.…”

“…It is unknown whether the cytoplasmic AR attracts signals from the surrounding stromal cells or sympathetic nerves located in the prostate cancer tumor microenvironment. The cytoplasmic AR binds to several proteins and activates several signaling molecules including SRC, RAS, MAPK, AKT, EGFR, and PI3K among others in prostate cancer [120][121][122]. As AR inhibitor ENZ leads to accumulation of high levels of cellular cytosolic AR, it is interesting to found out whether the high levels of cytosolic AR have any specific role in ENZ-induced NEPC transdifferentiation [123].…”