Differential but Concerted Expression of HSD17B2, HSD17B3, SHBG and SRD5A1 Testosterone Tetrad Modulate Therapy Response and Susceptibility to Disease Relapse in Patients with Prostate Cancer

Simple Summary Over the last two decades, our improved understanding of the pathobiology of androgen-addicted prostate cancer (PCa), and documented therapeutic advances/breakthroughs have not translated into any substantial or sustained curative benefit for patients treated with traditional ADT or novel immune checkpoint blockade therapeutics. This is invariably connected with the peculiar biology and intratumoral heterogeneity of PCa. Castration-resistant PCa, constituting ~30% of all PCa, remains a clinically enigmatic and therapeutically challenging disease sub-type, that is therapy-refractory and characterized by high risk for recurrence after initial response. Our findings highlight the role and exploitability of testosterone metabolic reprogramming in prostate TME for patient stratification and personalized/precision medicine based on the differential but concerted expression of molecular components of the proposed testosterone tetrad in patients with therapy-refractory, locally advanced, or recurrent PCa. The therapeutic exploitability and clinical feasibility of our proposed approach is suggested by our preclinical findings. Abstract Background: Testosterone plays a critical role in prostate development and pathology. However, the impact of the molecular interplay between testosterone-associated genes on therapy response and susceptibility to disease relapse in PCa patients remains underexplored. Objective: This study investigated the role of dysregulated or aberrantly expressed testosterone-associated genes in the enhanced dissemination, phenoconversion, and therapy response of treatment-resistant advanced or recurrent PCa. Methods: Employing a combination of multi-omics big data analyses, in vitro, ex vivo, and in vivo assays, we assessed the probable roles of HSD17B2, HSD17B3, SHBG, and SRD5A1-mediated testosterone metabolism in the progression, therapy response, and prognosis of advanced or castration-resistant PCa (CRPC). Results: Our bioinformatics-aided gene expression profiling and immunohistochemical staining showed that the aberrant expression of the HSD17B2, HSD17B3, SHBG, and SRD5A1 testosterone metabolic tetrad characterize androgen-driven PCa and is associated with disease progression. Reanalysis of the TCGA PRAD cohort (n = 497) showed that patients with SRD5A1-dominant high expression of the tetrad exhibited worse mid-term to long-term (≥5 years) overall survival, with a profoundly shorter time to recurrence, compared to those with low expression. More so, we observed a strong association between enhanced HSD17B2/SRD5A1 signaling and metastasis to distant lymph nodes (M1a) and bones (M1b), while upregulated HSD17B3/SHBG signaling correlated more with negative metastasis (M0) status. Interestingly, increased SHBG/SRD5A1 ratio was associated with metastasis to distant organs (M1c), while elevated SRD5A1/SHBG ratio was associated with positive biochemical recurrence (BCR) status, and shorter time to BCR. Molecular enrichment and protein–protein connectivity network analyses showed that the androgenic tetrad regulates testosterone metabolism and cross-talks with modulators of drug response, effectors of cell cycle progression, proliferation or cell motility, and activators/mediators of cancer stemness. Moreover, of clinical relevance, SHBG ectopic expression (SHBG_OE) or SRD5A1 knockout (sgSRD5A1) induced the acquisition of spindle fibroblastoid morphology by the round/polygonal metastatic PC-3 and LNCaP cells, attenuated their migration and invasion capability, and significantly suppressed their ability to form primary or secondary tumorspheres, with concomitant downregulation of stemness KLF4, OCT3/4, and drug resistance ABCC1, ABCB1 proteins expression levels. We also showed that metronomic dutasteride synergistically enhanced the anticancer effect of low-dose docetaxel, in vitro, and in vivo. Conclusion: These data provide proof of concept that re-reprogramming of testosterone metabolism through “SRD5A1 withdrawal” or “SHBG induction” is a workable therapeutic strategy for shutting down androgen-driven oncogenic signals, reversing treatment resistance, and repressing the metastatic/recurrent phenotypes of patients with PCa.