Serendipity, steroids and science

The androgen signaling pathway is probably the most important pathway in enabling prostate cancer progression but it also plays essential roles in numerous processes in normal physiology. Both testosterone and dihydrotestosterone are potent androgens that activate the androgen receptor (AR). The essentiality of the androgen pathway in prostate cancer is evidenced in part by the reactivation of AR in prostate cancer that becomes resistant to treatment by gonadal testosterone deprivation. Furthermore, steroid metabolic processes that allow the regeneration of potent androgens in prostate cancer tissues drive this treatment-resistant state, as is made clear by the survival benefit of blocking the synthesis of non-gonadal androgens, e.g., with abiraterone. Here, I narrate and review the process that led to a series of discoveries in androgen metabolism from our group. In this perspective and mechanistic narrative review, I give an honest description of the accidental nature of some of our initial findings, followed by data-driven hypothesis refinement and subsequent studies that illuminate elements of androgen metabolism, with a focus on metabolism of carbon 3, carbon 5 and carbon 17 of the steroid backbone.