Role of RPL39 in Metaplastic Breast Cancer

J Natl Cancer Inst. 2016 Dec 31;109(6):djw292. doi: 10.1093/jnci/djw292. Print 2017 Jun.

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.

MeSH terms

  • Adenosine Deaminase / genetics
  • Adenosine Deaminase / metabolism
  • Animals
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Movement / genetics
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Down-Regulation / drug effects
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use*
  • Female
  • Humans
  • Kaplan-Meier Estimate
  • Metaplasia
  • Mice
  • Mutation Rate
  • Neoplasm Transplantation
  • Nitrates / metabolism
  • Nitric Oxide Synthase Type II / antagonists & inhibitors
  • Nitric Oxide Synthase Type II / genetics
  • Nitric Oxide Synthase Type II / metabolism*
  • Nitrites / metabolism
  • RNA, Small Interfering / pharmacology
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Ribosomal Proteins / genetics*
  • Ribosomal Proteins / metabolism*
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / genetics
  • Survival Rate
  • Triple Negative Breast Neoplasms / genetics*
  • Triple Negative Breast Neoplasms / metabolism
  • Triple Negative Breast Neoplasms / pathology*
  • Ubiquitin C / metabolism
  • omega-N-Methylarginine / pharmacology
  • omega-N-Methylarginine / therapeutic use*

Substances

  • Enzyme Inhibitors
  • Nitrates
  • Nitrites
  • RNA, Small Interfering
  • RNA-Binding Proteins
  • Ribosomal Proteins
  • STAT3 Transcription Factor
  • Ubiquitin C
  • ribosomal protein L39
  • omega-N-Methylarginine
  • Nitric Oxide Synthase Type II
  • ADAR protein, human
  • Adenosine Deaminase