## 4 Discussion
This is particularly important because these stemness markers are implicated in dysregulated cell cycle, aberrant cell proliferation, enhanced cancer aggression, evasion of death signals, multidrug resistance, and worse prognosis [31]. Furthermore, contextualized within the genomics of cancer drug sensitivity, we also provided some proof of concept that re-reprogramming of testosterone metabolism via \"SRD5A1 withdrawal\" or \"SHBG induction\" is a workable therapeutic strategy for shutting down androgen-driven oncogenic signals, reversing cancer stem cell (CSC)-facilitated treatment resistance, and repressing the metastatic/recurrent phenotypes of patients with PCa (Figure 5). This is clinically significant as it further validates the burgeoning anticancer therapeutic concept that oncogene-addicted malignancies, including testosterone-driven PCa, present valuable actionable targets for therapeutic intervention with enhanced chance of achieving wide therapeutic windows. Our study demonstrates that aggressive PCa cells, especially metastatic and/or recurrent CRPC cells, exhibit a preferential dependence on androgen-driven oncogenic signaling pathway for maintaining their malignant phenotype, survival, and proliferation, regardless of the characteristic broad array of impairments within their genetic make-up, thus revealing a promising Achilles' heel of PCa [32]. We posit that the withdrawal of SRD5A1 or induction of SHBG in aggressive PCa cells elicits \"oncogenic shock\" [33], which entails the death of the testosterone tetrad-addicted cancerous cells upon inhibition of thecoprotein SRD5A1 to which they are seemingly addicted, or ectopic expression of the tumor suppressor SHBG to which they were estranged. This position is supported by our data showing significantly suppressed PC-3 cell viability, proliferation, motility (migration and invasion), and primary and secondary tumorsphere formation, with associated downregulation of TWIST1, SLUG, SNAIL, VIM, KLF4, OCT3/4, ABCB1, and ABCC1 upon \"SRD5A1 withdrawal\" by CRISPR knockout of SRD5A1, or \"SHBG induction\" using SHBG overexpression. The observed downregulation of both stemness and EMT markers by targeting components of the testosterone tetrad is consistent with contemporary knowledge of the complex interplay between cancer stemness and EMT. In concordant reports, it was recently demonstrated that \(\alpha\)2\(\beta\)1 integrin\({}^{\text{hi}}\) CD133+ prostate basal stem cells are characterized by enhanced expression of the transcription factor Zeb1, a vital inducer of EMT, both in silica, in vitro, and in vivo [34; 35]. Corollary to this, it has also been reported that these \"multipotent basal stem cells are exclusively located in juxta-urethral niches and function in a directed migratory way to generate epithelial progenitors\" [34], which is reminiscent of CSC-associated self-renewal, repopulation of cancerous prostate cells, and disease relapse after initial response. More so, PCa cells with mesenchymal traits have been shown to exhibit stem-cell-like phenotypes, such as upregulated expression of pluripotency factors OCT2, SOX2, and NANOG, with concomitant increase in clonogenicity, tumorsphere formation capability, and tumorigenicity in vivo [36]. Together, these accentuate the translational relevance of our results indicating that the molecular components of the testosterone tetrad are actionable, and may be exploited as an efficacious therapeutic strategy in patients with metastatic or recurrent PCa. It is also therapeutically relevant that, compared with PSA, the HSD17B2/HSD17B3/SHBG/SRD5A1 4-gene signature is capable of differentiating recurrent/nonresponsive from nonrecurrent/responsive PCa (Figure 6).