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Author Notes:

Correspondence to: Jenny C. Chang, MD, Houston Methodist Cancer Center, 6445 Main St., P24, Houston, TX 77030 (e-mail: jcchang@houstonmethodist.org)

The study funders had no role in the design of the study; the collection, analysis, or interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication.

Subjects:

Research Funding:

This work was funded by AUP-1010-0025 Chan Soon Shiong Institute of Advanced Health (JCC) and BCRF (JCC). Foundation Grants were awarded to JCC for studying novel therapeutics of breast cancer.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Oncology
  • TO-MESENCHYMAL TRANSITION
  • SQUAMOUS-CELL CARCINOMA
  • BIOCONDUCTOR PACKAGE
  • PROGNOSIS
  • SURVIVAL
  • THERAPY

Role of RPL39 in Metaplastic Breast Cancer

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Journal Title:

JNCI: Journal of the National Cancer Institute

Volume:

Volume 109, Number 6

Publisher:

, Pages djw292-djw292

Type of Work:

Article | Final Publisher PDF

Abstract:

Background: Metaplastic breast cancer is one of the most therapeutically challenging forms of breast cancer because of its highly heterogeneous and chemoresistant nature. We have previously demonstrated that ribosomal protein L39 (RPL39) and its gain-of-function mutation A14V have oncogenic activity in triple-negative breast cancer and this activity may be mediated through inducible nitric oxide synthase (iNOS). The function of RPL39 and A14V in other breast cancer subtypes is currently unknown. The objective of this study was to determine the role and mechanism of action of RPL39 in metaplastic breast cancer.Methods: Both competitive allele-specific and droplet digital polymerase chain reaction were used to determine the RPL39 A14V mutation rate in metaplastic breast cancer patient samples. The impact of RPL39 and iNOS expression on patient overall survival was estimated using the Kaplan-Meier method. Co-immunoprecipitation and immunoblot analyses were used for mechanistic evaluation of RPL39.Results: The RPL39 A14V mutation rate was 97.5% (39/40 tumor samples). High RPL39 (hazard ratio = 0.71, 95% confidence interval = 0.55 to 0.91, P = 006) and iNOS expression (P = 003) were associated with reduced patient overall survival. iNOS inhibition with the pan-NOS inhibitor NG-methyl-L-arginine acetate decreased in vitro proliferation and migration, in vivo tumor growth in both BCM-4664 and BCM-3807 patient-derived xenograft models (P = 04 and P = 02, respectively), and in vitro and in vivo chemoresistance. Mechanistically, RPL39 mediated its cancer-promoting actions through iNOS signaling, which was driven by the RNA editing enzyme adenosine deaminase acting on RNA 1.Conclusion: NOS inhibitors and RNA editing modulators may offer novel treatment options for metaplastic breast cancer.

Copyright information:

© The Author 2016. Published by Oxford University Press.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/).

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