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

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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.

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Acknowledgments

The authors would like to acknowledge Barretos Cancer Hospital, SP, for providing human specimens. We are also grateful to the Pathology Department of Barretos Cancer Hospital, SP, for TMA construction and analysis.

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Author notes

  1. Hellen Kuasne and Mateus C. Barros-Filho contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, Faculty of Medicine, São Paulo State University – UNESP, Botucatu, São Paulo, Brazil

    Hellen Kuasne

  2. CIPE - A.C. Camargo Cancer Center, São Paulo, Brazil

    Hellen Kuasne, Mateus C. Barros-Filho & Fábio A. Marchi

  3. Department of Surgery and Orthopedics and Department of Veterinary Clinic, School of Veterinary Medicine and Animal Science, UNESP, Botucatu, São Paulo, Brazil

    Sandra A. Drigo

  4. Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos and Diagnósticos da América (DASA), São Paulo, São Paulo, Brazil

    Cristovam Scapulatempo-Neto

  5. Department of Urology, Barretos Cancer Hospital, Barretos, São Paulo, Brazil

    Eliney F. Faria

  6. Department of Clinical Genetics, Vejle Hospital, Institute of Regional Health Research, University of Southern Denmark, Beriderbakken 4, 7100, Vejle, Denmark

    Silvia R. Rogatto

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  1. Hellen Kuasne
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Correspondence to Silvia R. Rogatto.

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The Institutional Human Research Ethics Committee (Barretos Cancer Hospital) approved the study (Protocol 363-2010).

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Kuasne, H., Barros-Filho, M.C., Marchi, F.A. et al. Nuclear loss and cytoplasmic expression of androgen receptor in penile carcinomas: role as a driver event and as a prognosis factor. Virchows Arch 473, 607–614 (2018). https://doi.org/10.1007/s00428-018-2404-3

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