YB-1 and MTA1 protein levels and not DNA or mRNA alterations predict for prostate cancer recurrence
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Christine Moore Sheridan1, Tristan R. Grogan2, Hao G. Nguyen1, Colette Galet3, Matthew B. Rettig3,4, Andrew C. Hsieh1,5,6 and Davide Ruggero1
1 Department of Urology, University of California, San Francisco, CA, USA
2 Statistic Core, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
3 Department of Medicine, VA Greater Los Angeles Healthcare System-West Los Angeles, CA, USA
4 Department of Urology, School of Medicine, University of California, Los Angeles, CA, USA
5 Department of Medicine, Division of Hematology/Oncology, University of California, San Francisco, CA, USA
6 Present address: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
Matthew B. Rettig, email:
Andrew C. Hsieh, email:
Davide Ruggero, email:
Keywords: translation control, prostate cancer, PSA recurrence, biomarker, YB-1
Received: January 27, 2015 Accepted: February 03, 2015 Published: March 03, 2015
Attempts to identify biomarkers to detect prostate tumorigenesis, and thus minimize prostate cancer progression and inform treatment decisions have primarily focused on alterations at the DNA and mRNA levels, ignoring alterations at the level of protein synthesis control. We have previously shown that the PI3K-AKT-mTOR pathway, frequently deregulated in prostate cancer, specifically induces the synthesis of proteins that contribute to metastasis, most notably YB-1 and MTA1, without altering mRNA levels thereby demonstrating the importance of translation control in driving the expression of these genes in cancer.Here, we analyze genomic sequencing and mRNA expression databases, as well as protein expression employing an annotated tissue microarray generated from 332 prostate cancer patients with 15 years of clinical follow-up to determine the combined prognostic capability of YB-1 and MTA1 alterations in forecasting prostate cancer outcomes. Remarkably, protein abundance, but not genomic or transcriptional alterations of YB-1 and MTA1, is predictive of disease recurrence, exhibiting a dose-dependent effect on time to PSA recurrence, an indicator of tumor relapse. Moreover, high protein levels of YB-1 and MTA1 are associated with a 3-fold increased risk for requiring future hormone therapy or radiation therapy. Importantly, YB-1 and MTA1 protein levels significantly increase the predictive capacity of a clinical model for prostate cancer recurrence. These findings demonstrate that protein abundance of YB-1 and MTA1, irrespective of DNA or mRNA status, can predict for prostate cancer relapse and uncover a vast underappreciated repository of biomarkers regulated at the level of protein expression.
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