Authors:
 Di Donato Marzia, Monaco Alessandra, Galasso Giovanni, Licitra Fabrizio, Bilancio Antonio, Auricchio Ferdinando, Castoria Gabriella, Migliaccio Antimo.
 
 
 Affiliations:
 Department of Precision Medicine, University of Campania “L. Vanvitelli” Via L. De Crecchio, 7- 80138 Naples.
 
 
 Abstract Body:
Prostate cancer (PC) is the most frequently diagnosed cancer among man and the second leading cause of deaths in men with cancer in Western countries. AR is commonly expressed in PC and plays a pivotal role in tumor growth. Therapies for advanced PC usually reduce or inhibit the androgen production. Alternatively, AR and its target genes can be antagonized by therapies that displace the AR binding to their cognate ligands. Most of the patients with advanced disease often exhibits drug-resistance and eventually develop hormone-refractory PC (HRPC) for which there is no efficient therapy. 
  Nevertheless, despite independence of hormone, high AR levels are expressed in HPRC, indicating that the receptor still exerts a role in tumor survival and progression, perhaps through its crosstalk with survival and metastatic programs. This notion is supported by the findings that AR signaling is still functional and can act as stimulator or as suppressor for proliferation and metastasis in HRPC. Additionally, many studies have supported a close relationship between PC progression and epidermal growth factor receptor (EGFR) or HER2 expression. 
 By combining different approaches in androgen-independent PC-derived C4-2B cells, which express AR, we have shown that AR signalling inhibits the mitogenic response elicited by EGF in these cells. 
 Treatment of cells with 10 nM of the synthetic androgen, R1881 does not affect cell proliferation. In contrast, C4-2B cells efficiently respond to EGF stimulation by increasing both BrdU incorporation and invasiveness. Interestingly, 10 nM R1881 completely inhibits the EGF mitogenic effect, leaving unaltered the growth factor effect on cell motility and invasiveness. This effect is likely caused by a delayed degradation of EGFR and a deregulation of the Ack1/clathrin HC internalization complex, with a persistence of the EGFR protein level upon combined treatment of cell with EGF and R1881. 
 In parallel, we observe that the activation state of Erk is more long lasting and stronger in cells challenged with EGF plus R1881. In this experimental setting, the cyclin/cdk inhibitor, p27, is retained in nuclei and cell proliferation reduced. The AR antagonist, Casodex reverses the R1881 inhibition of EGF-stimulated proliferation, indicating involvement of the receptor in the observed responses.
 In summary, androgens delay the down-regulation of EGFR induced by EGF, thus modifying and prolonging the EGFR dependent signaling in metastatic HRPC cells. 
 Our findings highlight the opposite role of AR in HRPC cells, as compared with the hormone sensitive PC cells. Understanding the mechanism(s) that underlie this effect on cell proliferation could lead to the development of new anti-cancer therapies for HRPCs that might improve the quality of life of the patients, as already currently happens by using the Intermittent Androgen Deprivation (IAD) therapy.
 
 
 Funding Acknowledgments:
 Program Valere 2020 (Vanvitelli per la Ricerca for RTDA and B -University of Campania “L. Vanvitelli”).
 
 
 Corresponding Author Email:
 pia.giovannelli@unicampania.it
 
 
 Conflict of Interest:
 Nothing to Disclose

THE ANDROGEN RECEPTOR (AR) IN ADVANCED PROSTATE CANCER (PC): A NEW CHANCE FOR CURE.