## 4 Discussion
More so, our finding is consistent with contemporary knowledge that human HSD17B2 suppresses the precursors of testosterone and DHT, namely C\({}_{19}\)17-ketosteroids dehydroepiandrosterone (DHEA), 5\(\alpha\)-androstanedione, and andarosterone, while HSD17B3-mediated conversion of DHEA to androst-5-ene3B,17B-diol contributes to upregulated synthesis of testicular testosterone [23; 24]. Furthermore, this study provides some pre-clinical evidence that the nonrandom, but concerted and well-calibrated interplay between the HSD17B2/HSD17B3/SHBG/SRD5A1 tetrad determines therapy response, facilitates disease progression and is relevant in clinical prognosis, especially with disease-driving roles attributed to SHBG and SRD5A1, while HSD17B2 and HSD17B3 are explicit passengers (Figures 2 and 3). This is consistent with reports of inversely correlated serum testosterone and SHBG levels, with proposed association between high serum SHBG and moderate decrease in the risk of PCa [25], as well as suggestions in a recent study that serum testosterone levels during ADT may be prognostic of the progression to CRPC in patients with metastatic PCa [26]. More so, \"recent assessment of CRPC cells has identified increased expression of steroidogenic enzymes such HSD3B1, HSD3B2, HSD17B3, AKR1C3, and SRD5A1, which may contribute to _de novo_ production of steroids and androgens\" [27]. For the first time, to the best of our knowledge, we also provided some evidence of a therapeutically actionable direct interaction between the testosterone tetrad, and that this distinct interaction is not just spatiotemporal, but functionally primed to drive cell cycle progression, enhance motility, cancer stemness, and resistance to therapy (Figure 4). In concordance with our findings that a high SRD5A1/SHBG ratio is associated with upregulated drug efflux proteins ALDH1A1, ABCB1, ABCC1, ABCG2, and markers of pluripotency, including KLF4, LIN28, OCT4, and SOX2, there are reports implicating enhanced drug-efflux in the resistance of CRPC to many chemotherapeutics, including Docetaxel, a drug of choice for hormone-naive advanced PCa in conjunction with ADT [27]. In fact, upregulated ABCB1 has been associated with the acquisition of a CRPC phenotype regardless of androgen-dependence status, as demonstrated by overexpression of ABCB1 in both the moderately metastatic, PSA negative, and hormone-insensitive DU145 and PSA positive, hormone-sensitive 22 RV1 cell lines when made Docetaxel-resistant [27; 28]. Other mechanisms of therapy resistance include dysregulated activity of cell cycle regulators, often overexpressed in PCa. In line with this, our study also found high SRD5A1/SHBGratio to be strongly associated with upregulated expression of CDK1 (the only CDK that is essential for cell cycle progression) and AURKA, a dyad that is characteristic of uncontrolled proliferation of cancerous cells, especially as the activation of CDK1 in complex with cyclin A/B is required and sufficient for entry into mitosis [29]. AURKA, which is localized in the centrosome during the S phase, is a serine/threonine kinase that plays a critical role in mitosis and cytokinesis, particularly because of its indispensability in centrosome maturation, spindle assembly, and spindle orientation [29]. Furthermore, in addition to promoting the activation of CDK1 and mitotic entry, especially after G2 phase arrest due to DNA damage, AURKA also prevents the proteasomal degradation of N-MYC, thus stabilizing it, and consequently promoting G1-S progression [29; 30]. The association of increased SRD5A1/SHBG ratio with upregulated expression of stemness markers LIN28, NANOG, KLF4, OCT4, and SOX2 is therapeutically relevant in terms of cancer stem-cell-targeting strategy, as it suggests an alternative approach to inhibiting signaling that are essential for the homeostasis and function of cancer stem cells, which are well documented drivers of cancer progression.