MYC Overexpression at the Protein and mRNA Level and Cancer Outcomes among Men Treated with Radical Prostatectomy for Prostate Cancer

Pettersson, Andreas; Gerke, Travis; Penney, Kathryn L.; Lis, Rosina T.; Stack, Edward C.; Pértega‐Gomes, Nelma; Zadra, Giorgia; Tyekucheva, Svitlana; Giovannucci, Edward; Mucci, Lorelei A.; Loda, Massimo

doi:10.1158/1055-9965.epi-17-0637

Cited by 30 publications

(30 citation statements)

References 28 publications

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“…Both PTEN protein loss and loss of 10q were individually associated with lethal disease, and the associations only changed modestly when mutually adjusting for 10q loss and PTEN loss (OR for 10q loss, 3.14; 95% CI, 1.13 to 8.75; OR for PTEN loss, 1.97; 95% CI, 1.04 to 3.73). Similarly, the association of 8q gain and lethal disease was slightly attenuated when adjusting for the 8q genes MYC or SQLE (SI Appendix, Table S3), although neither MYC protein nor MYC mRNA expression was associated with lethal disease in our cohorts (26). This indicates that single genes frequently altered in cancer cannot explain the association of chromosome-arm alterations with lethal disease.…”

Section: Significancementioning

confidence: 74%

Aneuploidy drives lethal progression in prostate cancer

Stopsack

Whittaker

Gerke

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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118

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Aneuploidy, defined as chromosome gains and losses, is a hallmark of cancer. However, compared with other tumor types, extensive aneuploidy is relatively rare in prostate cancer. Thus, whether numerical chromosome aberrations dictate disease progression in prostate cancer patients is not known. Here, we report the development of a method based on whole-transcriptome profiling that allowed us to identify chromosome-arm gains and losses in 333 primary prostate tumors. In two independent cohorts (n = 404) followed prospectively for metastases and prostate cancer-specific death for a median of 15 years, increasing extent of tumor aneuploidy as predicted from the tumor transcriptome was strongly associated with higher risk of lethal disease. The 23% of patients whose tumors had five or more predicted chromosome-arm alterations had 5.3 times higher odds of lethal cancer (95% confidence interval, 2.2 to 13.1) than those with the same Gleason score and no predicted aneuploidy. Aneuploidy was associated with lethality even among men with high-risk Gleason score 8-to-10 tumors. These results point to a key role of aneuploidy in driving aggressive disease in primary prostate cancer.

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Section: Significancementioning

confidence: 74%

Aneuploidy drives lethal progression in prostate cancer

Stopsack

Whittaker

Gerke

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

118

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“…In Foxp3/Tsc1 double-cKO mice, we used a more effective mTOR inhibitor, Torin1, with a low dose of a c-Myc inhibitor, 10058-F4, to block progression of mPIN to cancer, which may overcome tumor resistance to the mTOR inhibitor. Because both mTOR and c-MYC are frequently activated in prostate cancer (6,12,24,50), dual targeting strategies may be an effective therapeutic approach for blocking tumor progression and alleviating resistance to mTOR inhibitors.…”

Section: Dp Vp+lpmentioning

confidence: 99%

“…Nuclear protein expression of c-MYC, present in 97% of human prostate cancers, positively correlates with the proliferation rate and negatively with apoptotic count (12). In prostate cancer, activation of c-MYC cooperates with PI3K/AKT/mTOR signaling (13)(14)(15)(16), but the underlying molecular mechanisms remain unknown.…”

Section: Introductionmentioning

confidence: 99%

“…c-Myc is required for tumor initiation and progression of prostate cancers in Foxp3/Tsc1 double cKO mice c-MYC is the most commonly overexpressed oncogene in prostate cancers(12). Thus, we deleted c-Myc in the mouse prostate by crossing PB-Cre 4 mice with c-Myc flox/flox mice (SupplementaryFig.…”

mentioning

confidence: 99%

“…Ã , P < 0.05, two-tailed t test versus PB-Cre 4 control mice. H and I, Kaplan-Meier curves of mPIN and cancer incidences in cKO and PB-Cre 4 control mice (n ¼ 40/group) At 7,12,17,22,27,32,37,. and 43 weeks of age, 5 mice/per time point were sacrificed for pathologic analysis.…”

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confidence: 99%

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Loss of FOXP3 and TSC1 Accelerates Prostate Cancer Progression through Synergistic Transcriptional and Posttranslational Regulation of c-MYC

Wei

et al. 2019

Cancer Research

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Although c-MYC and mTOR are frequently activated proteins in prostate cancer, any interaction between the two is largely untested. Here, we characterize the functional cross-talk between FOXP3-c-MYC and TSC1-mTOR signaling during tumor progression. Deletion of Tsc1 in mouse embryonic fibroblasts (MEF) decreased phosphorylation of c-MYC at threonine 58 (pT58) and increased phosphorylation at serine 62 (pS62), an observation validated in prostate cancer cells. Conversely, inhibition of mTOR increased pT58 but decreased pS62. Loss of both FOXP3 and TSC1 in prostate cancer cells synergistically enhanced c-MYC expression via regulation of c-Myc transcription and protein phosphorylation. This crosstalk between FOXP3 and TSC1 appeared to be mediated by both the mTOR-4EBP1-c-MYC and FOXP3-c-MYC pathways. In mice, Tsc1 and Foxp3 double deletions in the prostate led to prostate carcinomas at an early age; this did not occur in these mice with an added c-Myc deletion. In addition, we observed synergistic antitumor effects of cotreating mice with inhibitors of mTOR and c-MYC in prostate cancer cells and in Foxp3 and Tsc1 double-mutant mice. In human prostate cancer, loss of nuclear FOXP3 is often accompanied by low expression of TSC1. Because loss of FOXP3 transcriptionally induces c-Myc expression and loss of TSC1 activates mTOR signaling, these data suggest cross-talk between FOXP3-c-MYC and TSC1-mTOR signaling that converges on c-MYC to regulate tumor progression. Coadministration of c-MYC and mTOR inhibitors may overcome the resistance to mTOR inhibition commonly observed in prostate cancer cells. Significance: These results establish the principle of a synergistic action of TSC1 and FOXP3 during prostate cancer progression and provide new therapeutic targets for patients who have prostate cancer with two signaling defects.

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