Profiling steroid hormone landscape of bladder cancer reveals depletion of intratumoural androgens to castration levels: a cross-sectional study

Abstract

<p><strong>Background: </strong>Bladder cancer is a highly over-represented disease in males. The involvement of sex steroids in bladder carcinogenesis and the utilisation of steroid hormone action as a therapeutic target have been frequently proposed. However, the intratumoural steroid milieu remains unclear.</p><p><strong>Methods: </strong>We used mass spectrometry and transcriptomic profiling to determine the levels of 23 steroid hormones and the expression of steroidogenic enzymes in primary tumours from patients who underwent transurethral resection (n = 24), and tumours and adjacent morphologically benign bladder tissues from treatment-naïve patients, who underwent radical cystectomy (n = 20). The corresponding steroids were determined from the patients' sera.</p><p><strong>Findings: </strong>Our results show that both bladder tumours and non-tumour tissues are androgen-poor, with DHT being virtually unquantifiable and testosterone at castration levels. Intratumoural enzymes that inactivate potent androgens (e.g., HSD17B2) exhibited similar tumour aggressiveness-linked downregulation, as reported in advanced forms of classical steroid-dependent cancers, whereas there was little change in the corresponding activating enzymes. Finally, our results suggest cancer aggressiveness-linked dissimilarities in steroid profiles; the patients with overall low circulating steroid levels and those with an association between androgen receptor expression and intratumoural testosterone levels in place had fewer recurrences than the rest.</p><p><strong>Interpretation: </strong>By revealing the steroid landscape of bladder cancer, our study not only underscores the androgen-poor nature of the malignancy but also identifies potential alterations in steroid profiles that are linked to disease aggressiveness.</p>