Expression of IGF/insulin receptor in prostate cancer tissue and progression to lethal disease.

Travis Gerke, Lorelei A Mucci, Michael Pollak, Zhe Li, Massimo Loda, Martin Gleave, Edward L Giovannucci, Stephen Finn, Howard D Sesso, Richard Flavin, Michelangelo Fiorentino, June M Chan, Thomas U Ahearn, Jennifer R Rider, Tarek A Bismar, Gregory L Judson, Ladan Fazli, Jennifer A Sinnott, Rebecca E Graff, Cindy Ke Zhou, Ericka M Ebot, Andreas Pettersson, Sam Peisch

Journal: Carcinogenesis 2019;39(12):1431-1437

PMID: 30165429

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Abstract

Circulating insulin-like growth factor-1 (IGF-1) is consistently associated with prostate cancer risk. IGF-1 binds to IGF-1 receptor (IGF1R) and insulin receptor (IR), activating cancer hallmark pathways. Experimental evidence suggests that TMPRSS2:ERG may interact with IGF/insulin signaling to influence progression. We investigated IGF1R and IR expression and its association with lethal prostate cancer among 769 men. Protein expression of IGF1R, IR and ERG (i.e. a surrogate of ERG fusion genes) were assayed by immunohistochemistry. Cox models estimated hazard ratios (HR) and 95% confidence intervals (CI) adjusted for clinical characteristics. Among patients, 29% had strong tumor IGF1R expression and 10% had strong IR expression. During a mean follow-up of 13.2 years through 2012, 80 men (11%) developed lethal disease. Tumors with strong IGF1R or IR expression showed increased cell proliferation, decreased apoptosis and a higher prevalence of ERG. In multivariable models, strong IGF1R was associated with a borderline increased risk of lethal prostate cancer (HR 1.7; 95% CI 0.9-3.1). The association appeared greater in ERG-positive tumors (HR 2.8; 95% CI 0.9-8.4) than in ERG-negative tumors (HR 1.3; 95% CI 0.6-3.0, p-heterogeneity 0.08). There was no association between IR and lethal prostate cancer (HR 0.8; 95% CI 0.4-1.9). These results suggest that tumor IGF1R expression may play a role in prostate cancer progression to a lethal phenotype and that ERG-positive tumors may be more sensitive to IGF signaling. These data may improve our understanding of IGF signaling in prostate cancer and suggest therapeutic options for disease subtypes.

Address: Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.; Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.; Vancouver Prostate Center, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.; Department of Pathology and Laboratory Medicine, University of Calgary and Calgary Laboratory Services, Calgary, Alberta, Canada.; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.; Boston University School of Public Health, Boston, MA, USA.; Pathology Unit, Addarii Institute, S. Orsola-Malpighi Hospital, Bologna, Italy.; Department of Histopathology Research, Trinity College, Dublin, Ireland.; Divisions of Preventive Medicine and Aging, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.; Cancer Prevention Research Unit, Departments of Medicine and Oncology, Lady Davis Research Institute of the Jewish General Hospital and McGill University, Montreal, Quebec, Canada.

DOI: 10.1093/carcin/bgy112