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

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


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.

Published In Carcinogenesis
Date Aug 24, 2018
DOI 10.1093/carcin/bgy112


Ahearn TU*, Peisch S*, Pettersson A, Ebot EM, Zhou K, Graff RE, Sinnott JA, Fazli L, Judson GJ, Bismar TA, Rider JR, Gerke TA, Chan JM, Fiorentino M, Flavin R, Sesso HD, Finn S, Giovannucci EL, Gleave M, Loda M, Li Z, Pollak M**, Mucci LA**. Expression of IGF/insulin receptor in prostate cancer tissue and progression to lethal disease. Carcinogenesis 2018; In press.