Role of RPL39 in Metaplastic Breast Cancer

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-n...

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Published in:	JNCI : Journal of the National Cancer Institute Vol. 109; no. 6; p. djw292
Main Authors:	Dave, Bhuvanesh, Gonzalez, Daniel D, Liu, Zhi-Bin, Li, Xiaoxian, Wong, Helen, Granados, Sergio, Ezzedine, Nadeer E, Sieglaff, Douglas H, Ensor, Joe E, Miller, Kathy D, Radovich, Milan, KarinaEtrovic, Agda, Gross, Steven S, Elemento, Olivier, Mills, Gordon B, Gilcrease, Michael Z, Chang, Jenny C
Format:	Journal Article
Language:	English
Published:	United States Oxford University Press 01-06-2017
Subjects:	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 omega-N-Methylarginine - pharmacology omega-N-Methylarginine - therapeutic use Ribosomal Proteins - genetics Ribosomal Proteins - metabolism RNA, Small Interfering - pharmacology RNA-Binding Proteins - genetics RNA-Binding Proteins - metabolism Signal Transduction - genetics STAT3 Transcription Factor - metabolism Survival Rate Triple Negative Breast Neoplasms - genetics Triple Negative Breast Neoplasms - metabolism Triple Negative Breast Neoplasms - pathology Ubiquitin C - metabolism
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Summary:	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. 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. 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 N -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. NOS inhibitors and RNA editing modulators may offer novel treatment options for metaplastic breast cancer.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0027-8874 1460-2105
DOI:	10.1093/jnci/djw292