Colibactin Exerts Androgen-dependent and -independent Effects on Prostate Cancer PMID: 39547899

ADC Targets in Oncology

2026-04-10

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

Eur Urol Oncol. 2025 Jun;8(3):716-730. doi: 10.1016/j.euo.2024.10.015.

Raag Agrawal ¹ , Sarah Al-Hiyari ² , Rupert Hugh-White ² , Robert Hromas ³ , Yash Patel ² , Elizabeth A Williamson ³ , Mohammed F E Mootor ² , Alfredo Gonzalez ¹ , Jianmin Fu ⁴ , Roni Haas ¹ , Madison Jordan ¹ , Brian L Wickes ⁵ , Ghouse Mohammed ⁶ , Mao Tian ¹ , Molly J Doris ⁷ , Christian Jobin ⁸ , Kevin M Wernke ⁹ , Yu Pan ⁶ , Takafumi N Yamaguchi ² , Seth B Herzon ⁹ , Paul C Boutros ¹⁰ , Michael A Liss ¹¹

Affiliations

1. Department of Human Genetics, University of California-Los Angeles, Los Angeles, CA, USA; Department of Urology, University of California-Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California-Los Angeles, Los Angeles, CA, USA.
2. Department of Human Genetics, University of California-Los Angeles, Los Angeles, CA, USA; Department of Urology, University of California-Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California-Los Angeles, Los Angeles, CA, USA; Institute for Precision Health, University of California-Los Angeles, Los Angeles, CA, USA.
3. Division of Hematology and Medical Oncology, Department of Medicine and the Mays Cancer Center, University of Texas Health-San Antonio, San Antonio, TX, USA.
4. Department of Microbiology and Immunology, University of Texas Health-San Antonio, San Antonio, TX, USA.
5. Department of Microbiology, Immunology, and Molecular Genetics, University of Texas, San Antonia, TC, USA.
6. Office of Health Informatics and Analytics, University of California-Los Angeles, Los Angeles, CA, USA.
7. Department of Urology, University of Texas Health-San Antonio, San Antonio, TX, USA.
8. Departments of Medicine, Infectious Diseases and Immunology, and Anatomy and Cell Physiology, University of Florida, Gainesville, FL, USA.
9. Department of Chemistry, Yale University, New Haven, CT, USA; Department of Pharmacology, Yale School of Medicine, New Haven, CT, USA.
10. Department of Human Genetics, University of California-Los Angeles, Los Angeles, CA, USA; Department of Urology, University of California-Los Angeles, Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center, University of California-Los Angeles, Los Angeles, CA, USA; Institute for Precision Health, University of California-Los Angeles, Los Angeles, CA, USA; Department of Medical Biophysics, University of Toronto, Toronto, Canada.
11. Department of Urology, University of Texas Health-San Antonio, San Antonio, TX, USA. Electronic address: [email protected].

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.