Colibactin Exerts Androgen-dependent and -independent Effects on Prostate Cancer.

Abstract

Background and objective: The etiology of prostate cancer (PC) is multifactorial and poorly understood. It has been suggested that colibactin-producing Escherichia coli positive for the pathogenicity island pks (pks⁺) initiate cancers via induction of genomic instability. In PC, androgens promote oncogenic translocations. Our aim was to investigate the association of pks⁺E. coli with PC diagnosis and molecular architecture, and its relationship with androgens.

Methods: We quantified the association of pks⁺E. coli with PC diagnosis in a volunteer-sampled 235-person cohort from two institutional practices (UT San Antonio). We then used colibactin 742 and DNA/RNA sequencing to evaluate the effects of colibactin 742, dihydrotestosterone (DHT), and their combination in vitro.

Key findings and limitations: Colibactin exposure was positively associated with PC diagnosis (p = 0.04) in our clinical cohort, and significantly increased replication fork stalling and fusions in vitro (p < 0.01). Combined in vitro exposure to colibactin 742 and DHT induced more somatic mutations of all types than exposure to either alone. The combination also elicited kataegis, with a higher density of somatic point mutations. Laboratory analyses were conducted using a single cell line, which limited our ability to fully recapitulate the complexity of PC etiology.

Conclusions and clinical implications: Our findings are consistent with synergistic induction of genome instability and kataegis by colibactin 742 and DHT in cell culture. Colibactin-producing pks⁺ E. coli may plausibly contribute to PC etiology.

Patient summary: We investigated whether a bacterial toxin that is linked to colon cancer can also cause prostate cancer. Our results support this idea by showing a link between the toxin and prostate cancer diagnosis in a large patient population. We also found that this toxin causes genetic dysfunction in prostate cancer cells when combined with testosterone.