Projects per year
Abstract
Inhibiting the androgen receptor (AR), a ligand-activated transcription Increased ERV expression led to accumulation of double-stranded RNA factor, with androgen deprivation therapy is a standard-of-care treatment and a “viral mimicry” response characterized by activation of IFN signal-for metastatic prostate cancer. Paradoxically, activation of AR can also ing, upregulation of MHC class I molecules, and enhanced recognition of inhibit the growth of prostate cancer in some patients and experimen- murine prostate cancer cells by CD8+ T cells. Positive associations between tal systems, but the mechanisms underlying this phenomenon are poorly AR activity and ERVs/antiviral pathways were evident in patient transcripunderstood. This study exploited a potent synthetic androgen, methyl- tomic data, supporting the clinical relevance of our findings. Collectively, testosterone (MeT), to investigate AR agonist-induced growth inhibition. our study reveals that the potent androgen MeT can increase the immunoMeT strongly inhibited growth of prostate cancer cells expressing AR, genicity of prostate cancer cells via a viral mimicry response, a finding that but not AR-negative models. Genes and pathways regulated by MeT were has potential implications for the development of strategies to sensitize this highly analogous to those regulated by DHT, although MeT induced a cancer type to immunotherapies. quantitatively greater androgenic response in prostate cancer cells. MeT Significance:Our study demonstrates that potent androgen stimulation potently downregulated DNA methyltransferases, leading to global DNA of prostate cancer cells can elicit a viral mimicry response, resulting hypomethylation. These epigenomic changes were associated with dys- in enhanced IFN signaling. This finding may have implications for the regulation of transposable element expression including upregulation of development of strategies to sensitize prostate cancer to immunotherapies. endogenous retrovirus (ERV) transcripts after sustained MeT treatment.
Original language | English |
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Pages (from-to) | 706-724 |
Number of pages | 19 |
Journal | Cancer Research Communications |
Volume | 2 |
Issue number | 7 |
DOIs | |
Publication status | Published - Jul 2022 |
Projects
- 6 Finished
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New combination therapies for castration-resistant prostate cancer
Lawrence, M. (Primary Chief Investigator (PCI)), Risbridger, G. (Associate Investigator (AI)), Azad, A. (Associate Investigator (AI)) & Taylor, R. (Associate Investigator (AI))
15/02/19 → 14/02/23
Project: Research
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Giving prostate cancer enough rope with supraphysiologic testosterone
Lawrence, M. (Primary Chief Investigator (PCI)), Risbridger, G. (Chief Investigator (CI)) & Joshua, A. M. (Chief Investigator (CI))
National Health and Medical Research Council (NHMRC) (Australia)
1/01/19 → 31/12/21
Project: Research
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Transforming endocrine therapy for breast and prostate cancer
Tilley, W. D. (Primary Chief Investigator (PCI)), Risbridger, G. (Chief Investigator (CI)), Carroll, J. S. (Chief Investigator (CI)), Lim, E. (Chief Investigator (CI)), Clark, S. J. (Chief Investigator (CI)), Hicky, T. (Chief Investigator (CI)) & Selth, L. A. (Chief Investigator (CI))
National Breast Cancer Foundation
1/11/18 → 30/10/22
Project: Research