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Cancer Genes and Networks

Telomere DNA Damage Signaling Regulates Prostate Cancer Tumorigenesis

Jianchun Wu and David L. Crowe
Jianchun Wu
University of Illinois Cancer Center, Chicago, Illinois.
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David L. Crowe
University of Illinois Cancer Center, Chicago, Illinois.
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  • For correspondence: dlcrowe@uic.edu
DOI: 10.1158/1541-7786.MCR-19-1129 Published September 2020
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Abstract

Telomere shortening has been demonstrated in benign prostatic hypertrophy (BPH), which is associated with prostate epithelial cell senescence. Telomere shortening is the most frequently observed genetic alteration in prostatic intraepithelial neoplasia, and is associated with poor clinical outcomes in prostate cancer. Gene expression database analysis revealed decreased TRF2 expression during malignant progression of the prostate gland. We reasoned that reduced TRF2 expression in prostate epithelium, by activating the telomere DNA damage response, would allow us to model both benign and malignant prostate disease. Prostate glands with reduced epithelial TRF2 expression developed age- and p53-dependent hypertrophy, senescence, ductal dilation, and smooth muscle hyperplasia similar to human BPH. Prostate tumors with reduced TRF2 expression were classified as high-grade androgen receptor–negative adenocarcinomas, which exhibited decreased latency, increased proliferation, and distant metastases. Prostate cancer stem cells with reduced TRF2 expression were highly tumorigenic and maintained telomeres both by telomerase and alternative lengthening (ALT). Telomerase inhibition in prostate glands with reduced TRF2 expression produced significant reduction in prostate tumor incidence by halting progression at intraepithelial neoplasia (PIN). These lesions were highly differentiated, exhibited low proliferation index, and high apoptotic cell fraction. Prostate tumors with reduced TRF2 expression and telomerase inhibition failed to metastasize and did not exhibit ALT.

Implications: Our results demonstrate that the telomere DNA damage response regulates BPH, PIN, and prostate cancer and may be therapeutically manipulated to prevent prostate cancer progression.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Mol Cancer Res 2020;18:1326–39

  • Received November 24, 2019.
  • Revision received March 30, 2020.
  • Accepted May 21, 2020.
  • Published first May 28, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Research: 18 (9)
September 2020
Volume 18, Issue 9
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Telomere DNA Damage Signaling Regulates Prostate Cancer Tumorigenesis
Jianchun Wu and David L. Crowe
Mol Cancer Res September 1 2020 (18) (9) 1326-1339; DOI: 10.1158/1541-7786.MCR-19-1129

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Telomere DNA Damage Signaling Regulates Prostate Cancer Tumorigenesis
Jianchun Wu and David L. Crowe
Mol Cancer Res September 1 2020 (18) (9) 1326-1339; DOI: 10.1158/1541-7786.MCR-19-1129
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Molecular Cancer Research
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