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YB-1 and MTA1 protein levels and not DNA or mRNA alterations predict for prostate cancer recurrence.

Sheridan CM, Grogan TR, Nguyen HG, Galet C, Rettig MB, Hsieh AC, Ruggero D - Oncotarget (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, University of California, San Francisco, CA, USA.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

YB-1 and MTA1 protein levels are predictors of PSA recurrence-free survival and future need for androgen deprivation therapy or radiation therapy(A) Univariate and multivariate analysis of pre- and postoperative features for the prediction of PSA progression in 332 patients treated with radical prostatectomy for clinically localized prostate cancer. (B) Kaplan-Meier analysis demonstrates that high protein expression levels of YB-1 and MTA1 within prostatic intraepithelial neoplasia lesions are associated with worse PSA recurrence-free survival. (C) Total number and percentage of patients who required androgen deprivation therapy or radiation therapy post-prostatectomy (post-RP) based on high or low protein levels of YB-1 and MTA1 (Chi-squared test).
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Figure 2: YB-1 and MTA1 protein levels are predictors of PSA recurrence-free survival and future need for androgen deprivation therapy or radiation therapy(A) Univariate and multivariate analysis of pre- and postoperative features for the prediction of PSA progression in 332 patients treated with radical prostatectomy for clinically localized prostate cancer. (B) Kaplan-Meier analysis demonstrates that high protein expression levels of YB-1 and MTA1 within prostatic intraepithelial neoplasia lesions are associated with worse PSA recurrence-free survival. (C) Total number and percentage of patients who required androgen deprivation therapy or radiation therapy post-prostatectomy (post-RP) based on high or low protein levels of YB-1 and MTA1 (Chi-squared test).

Mentions: We next determined the independent predictive value of YB-1 and MTA1 levels on the clinically important outcome of PSA recurrence, which is typically the first indicator of disease relapse in prostate cancer patients after surgery. As expected, pathologic features such as pre-operative PSA levels, Gleason score, presence of ECE, presence of SVI, and positive surgical margins were all significant predictors of PSA recurrence by both univariate and multivariate analyses (Figure 2A). Strikingly, a univariate analysis revealed a significant risk for PSA recurrence in patients whose adjacent normal, PIN, and prostate cancer tissues expressed high YB-1 protein levels (adjacent normal: HR 1.21, 95% CI 1.04-1.43, P = 0.01; PIN: HR 1.35, 95% CI 1.12-1.63, P = 0.002; cancer: HR 1.20, 95% CI 1.02-1.40, P = 0.02) (Figure 2A). For MTA1, the univariate analysis showed an increased risk for PSA recurrence associated with high protein levels in adjacent normal and PIN, but not prostate cancer tissues (adjacent normal: HR 1.24, 95% CI 1.05-1.47, P = 0.01; PIN: HR 1.30, 95% CI 1.06-1.61, P = 0.012; cancer: HR 1.14, 95% CI 0.98-1.34, P = 0.098) (Figure 2A). The positive association between high YB-1 and MTA1 protein levels in adjacent normal tissues and PSA-recurrence raises the possibility that non-cell autonomous effects elicited by the surrounding microenvironment may also influence the expression of these proteins. Interestingly, these findings also demonstrate that YB-1 and MTA1 protein levels are most predictive for PSA recurrence in a particular tissue type. For example, out of all the tissue types analyzed including adjacent normal, PIN, and prostate cancer, high protein levels of YB-1 and MTA1 in PIN lesions were the most significantly associated with an increased risk for PSA recurrence. The potential predictive capacity of YB-1 and MTA1 protein levels as biomarkers in PIN for PSA recurrence is further supported by a subsequent multivariate analysis, which unlike the univariate analysis, controls for clinical and pathological factors. In particular, increased levels of YB-1 and MTA1 in the PIN samples correlated with the highest risk for PSA recurrence following radical prostatectomy, as compared with YB-1 and MTA1 protein levels in adjacent normal and prostate cancer tissues (PIN: HR = 1.52, 95% CI 1.24-1.85, P < 0.001 and HR 1.46, 95% CI 1.18-1.81, P < 0.001, respectively; adjacent normal: HR 1.28, 95% CI 1.08-1.51, P = 0.004 and HR 1.2, 95% CI 1.01-1.42, P = 0.03, respectively; cancer: HR 1.15, 95% CI 0.97-1.34, P = 0.11 and HR 1.17, 95% CI 0.99-1.38, P = 0.06, respectively) (Figure 2A). Thus, protein levels of YB-1 and MTA1 in PIN lesions from radical prostatectomy tissue samples are the most predictive for PSA recurrence compared to other tissue types. Moreover, these findings raise the intriguing possibility that acquisition of metastatic potential is an early event in prostate cancer development.


YB-1 and MTA1 protein levels and not DNA or mRNA alterations predict for prostate cancer recurrence.

Sheridan CM, Grogan TR, Nguyen HG, Galet C, Rettig MB, Hsieh AC, Ruggero D - Oncotarget (2015)

YB-1 and MTA1 protein levels are predictors of PSA recurrence-free survival and future need for androgen deprivation therapy or radiation therapy(A) Univariate and multivariate analysis of pre- and postoperative features for the prediction of PSA progression in 332 patients treated with radical prostatectomy for clinically localized prostate cancer. (B) Kaplan-Meier analysis demonstrates that high protein expression levels of YB-1 and MTA1 within prostatic intraepithelial neoplasia lesions are associated with worse PSA recurrence-free survival. (C) Total number and percentage of patients who required androgen deprivation therapy or radiation therapy post-prostatectomy (post-RP) based on high or low protein levels of YB-1 and MTA1 (Chi-squared test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480693&req=5

Figure 2: YB-1 and MTA1 protein levels are predictors of PSA recurrence-free survival and future need for androgen deprivation therapy or radiation therapy(A) Univariate and multivariate analysis of pre- and postoperative features for the prediction of PSA progression in 332 patients treated with radical prostatectomy for clinically localized prostate cancer. (B) Kaplan-Meier analysis demonstrates that high protein expression levels of YB-1 and MTA1 within prostatic intraepithelial neoplasia lesions are associated with worse PSA recurrence-free survival. (C) Total number and percentage of patients who required androgen deprivation therapy or radiation therapy post-prostatectomy (post-RP) based on high or low protein levels of YB-1 and MTA1 (Chi-squared test).
Mentions: We next determined the independent predictive value of YB-1 and MTA1 levels on the clinically important outcome of PSA recurrence, which is typically the first indicator of disease relapse in prostate cancer patients after surgery. As expected, pathologic features such as pre-operative PSA levels, Gleason score, presence of ECE, presence of SVI, and positive surgical margins were all significant predictors of PSA recurrence by both univariate and multivariate analyses (Figure 2A). Strikingly, a univariate analysis revealed a significant risk for PSA recurrence in patients whose adjacent normal, PIN, and prostate cancer tissues expressed high YB-1 protein levels (adjacent normal: HR 1.21, 95% CI 1.04-1.43, P = 0.01; PIN: HR 1.35, 95% CI 1.12-1.63, P = 0.002; cancer: HR 1.20, 95% CI 1.02-1.40, P = 0.02) (Figure 2A). For MTA1, the univariate analysis showed an increased risk for PSA recurrence associated with high protein levels in adjacent normal and PIN, but not prostate cancer tissues (adjacent normal: HR 1.24, 95% CI 1.05-1.47, P = 0.01; PIN: HR 1.30, 95% CI 1.06-1.61, P = 0.012; cancer: HR 1.14, 95% CI 0.98-1.34, P = 0.098) (Figure 2A). The positive association between high YB-1 and MTA1 protein levels in adjacent normal tissues and PSA-recurrence raises the possibility that non-cell autonomous effects elicited by the surrounding microenvironment may also influence the expression of these proteins. Interestingly, these findings also demonstrate that YB-1 and MTA1 protein levels are most predictive for PSA recurrence in a particular tissue type. For example, out of all the tissue types analyzed including adjacent normal, PIN, and prostate cancer, high protein levels of YB-1 and MTA1 in PIN lesions were the most significantly associated with an increased risk for PSA recurrence. The potential predictive capacity of YB-1 and MTA1 protein levels as biomarkers in PIN for PSA recurrence is further supported by a subsequent multivariate analysis, which unlike the univariate analysis, controls for clinical and pathological factors. In particular, increased levels of YB-1 and MTA1 in the PIN samples correlated with the highest risk for PSA recurrence following radical prostatectomy, as compared with YB-1 and MTA1 protein levels in adjacent normal and prostate cancer tissues (PIN: HR = 1.52, 95% CI 1.24-1.85, P < 0.001 and HR 1.46, 95% CI 1.18-1.81, P < 0.001, respectively; adjacent normal: HR 1.28, 95% CI 1.08-1.51, P = 0.004 and HR 1.2, 95% CI 1.01-1.42, P = 0.03, respectively; cancer: HR 1.15, 95% CI 0.97-1.34, P = 0.11 and HR 1.17, 95% CI 0.99-1.38, P = 0.06, respectively) (Figure 2A). Thus, protein levels of YB-1 and MTA1 in PIN lesions from radical prostatectomy tissue samples are the most predictive for PSA recurrence compared to other tissue types. Moreover, these findings raise the intriguing possibility that acquisition of metastatic potential is an early event in prostate cancer development.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, University of California, San Francisco, CA, USA.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus