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Role of RPL39 in Metaplastic Breast Cancer
Bhuvanesh Dave1, Daniel D Gonzalez1, Zhi-Bin Liu1
1Affiliations of authors: Houston Methodist Cancer Center, Houston, TX (BD, DDG, ZBL, HW, SG, DHS, JEE, JCC); Division of Basic Science Research, Department of Systems Biology (NEE, AKE, GBM), and Division of Pathology/Lab Medicine, Department of Pathology (MZG), The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Breast Surgery, Shanghai Cancer Center and Cancer Institute of Fudan University, Shanghai, China (ZBL); Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA (XL); Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY (OE); Joan and Sanford I. Weill Medical School of Cornell University, New York, NY (SSG); Department of Medicine, Indiana University Medical School, Indianapolis, IN (KDM); Departments of Surgery and Medical and Molecular Genetics, IU Center for Computational Biology and Bioinformatics, Indianapolis, IN (MR).
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.
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