## 1 Introduction
### Clinical and Molecular Characteristics of Prostate Cancer  
Prostate cancer (PCa) is the most diagnosed non-cutaneous male malignancy and a leading cause of cancer-related deaths globally, having an annual incidence and mortality rate of 7.1 and 3.8%, respectively, in 2018, and a projected increase of \(\sim\)1.8-fold in incidence and 2.1-fold in mortality by the year 2040 [1]. It has been suggested that one in every three patients with PCa will develop metastatic or recurrent disease within 2 years of initial diagnosis, one in every five patients with metastatic or recurrent disease evolve into castration-resistant PCa (CRPC) by fifth year of follow-up, and the median survival of patients after developing castration resistance is \(\sim\)14 months [2;3]. Despite this soaring incidence, high mortality burden, and enhanced risk of disease progression among patients with PCa, the biomechanics underlying its development and progression remain largely unclear. In the last decade, there has been a renaissance and increased exploration of the role of androgens, including testosterone and its derivative, dihydrotestosterone (DHT), in the cancerization of normal prostate cells, disease progression, and poor prognosis in patients with PCa; this may not be unconnected with the androgen-regulated nature of the prostate, as well as the indispensability of androgens in the regulation of uptake and metabolism of lipid and insulin [4]. Against this background, PCa remains a profoundly heterogeneous and complex pathology, such that the clinicopathological characteristics of patients at diagnosis fails to adequately anticipate tumor clinical phenotype, and needle biopsy-associated undersampling undermines the reliability of biopsy findings as truly reflective of disease course or cancer aggressiveness. All these necessitate the discovery and validation of actionable molecular biomarkers that provide clinically objective measures of the tumor biology, improve the patients' classification and stratification, and inform therapeutic decision-making (see Graphic Abstract). Testosterone Metabolism, Therapy Response, and Susceptibility to Disease Relapse in Patients with PCa  
Despite diagnostic and therapeutic advances made in the last 3 decades, PCa morbidity remains high, about 30% of patients present with advanced or metastatic disease, and mortality is unabating. Following [PERSON] concept of androgen-dependence introduced in 1972, androgen deprivation therapy (ADT) has remained the standard of care for initial management of advanced, metastatic, or recurrent disease; however, development of CRPC within 2-3 years of ADT initiation continues to confound the promise of any therapeutic success in prostate cancer clinics [2; 3]. A principal characteristic of PCa cells is their profound dependence on or addiction to androgens. Androgens are essential for prostate physiology in men. As already alluded, the principal male androgens are testosterone, produced by testicular interstitial or Leydig cells, and DHT, derived from steroid-5-\(\alpha\)-reductase (SRD5A1)-mediated catabolism of testosterone in peripheral tissues. SRD5A messenger RNA expression profiling in several publicly available cancer datasets show that, compared with nontumor prostate tissues, SRD5A1 is upregulated in primary and metastatic PCa, and the activation of the driver oncogene androgen receptor (AR) induced a 2- to 4-fold overexpression of SRD5A1 in androgen-responsive PCa cells [5]. In circulation, testosterone is primarily bound to sex-hormone-binding globulin (SHBG), while the free or unbound testosterone is the active and most bioavailable form [6]. The internalization and endogenous expression of SHBG has been shown to increase DHT uptake, prolong the expression of testosterone-responsive genes, and is associated with clinicopathological traits that are characteristic of disease progression.