Role of RPL39 in Metaplastic Breast Cancer

Bhuvanesh Dave, Daniel D. Gonzalez, Zhi Bin Liu, Xiaoxian Li, Helen Wong, Sergio Granados, Nadeer E. Ezzedine, Douglas H. Sieglaff, Joe E. Ensor, Kathy Miller, Milan Radovich, Agda KarinaEtrovic, Steven S. Gross, Olivier Elemento, Gordon B. Mills, Michael Z. Gilcrease, Jenny C. Chang

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish (US)
JournalJournal of the National Cancer Institute
Volume109
Issue number6
DOIs
StatePublished - Jun 1 2017

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Breast Neoplasms
Nitric Oxide Synthase Type II
RNA Editing
Mutation Rate
Triple Negative Breast Neoplasms
ribosomal protein L39
Neoplasms
Adenosine Deaminase
Survival
Immunoprecipitation
Heterografts
Arginine
Acetates
Alleles
RNA
Confidence Intervals
Polymerase Chain Reaction
Mutation
Enzymes
Growth

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Dave, B., Gonzalez, D. D., Liu, Z. B., Li, X., Wong, H., Granados, S., ... Chang, J. C. (2017). Role of RPL39 in Metaplastic Breast Cancer. Journal of the National Cancer Institute, 109(6). https://doi.org/10.1093/jnci/djw292

Role of RPL39 in Metaplastic Breast Cancer. / 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; Radovich, Milan; KarinaEtrovic, Agda; Gross, Steven S.; Elemento, Olivier; Mills, Gordon B.; Gilcrease, Michael Z.; Chang, Jenny C.

In: Journal of the National Cancer Institute, Vol. 109, No. 6, 01.06.2017.

Research output: Contribution to journalArticle

Dave, B, Gonzalez, DD, Liu, ZB, Li, X, Wong, H, Granados, S, Ezzedine, NE, Sieglaff, DH, Ensor, JE, Miller, K, Radovich, M, KarinaEtrovic, A, Gross, SS, Elemento, O, Mills, GB, Gilcrease, MZ & Chang, JC 2017, 'Role of RPL39 in Metaplastic Breast Cancer', Journal of the National Cancer Institute, vol. 109, no. 6. https://doi.org/10.1093/jnci/djw292
Dave B, Gonzalez DD, Liu ZB, Li X, Wong H, Granados S et al. Role of RPL39 in Metaplastic Breast Cancer. Journal of the National Cancer Institute. 2017 Jun 1;109(6). https://doi.org/10.1093/jnci/djw292
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 ; Radovich, Milan ; KarinaEtrovic, Agda ; Gross, Steven S. ; Elemento, Olivier ; Mills, Gordon B. ; Gilcrease, Michael Z. ; Chang, Jenny C. / Role of RPL39 in Metaplastic Breast Cancer. In: Journal of the National Cancer Institute. 2017 ; Vol. 109, No. 6.
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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.",
author = "Bhuvanesh Dave and Gonzalez, {Daniel D.} and Liu, {Zhi Bin} and Xiaoxian Li and Helen Wong and Sergio Granados and Ezzedine, {Nadeer E.} and Sieglaff, {Douglas H.} and Ensor, {Joe E.} and Kathy Miller and Milan Radovich and Agda KarinaEtrovic and Gross, {Steven S.} and Olivier Elemento and Mills, {Gordon B.} and Gilcrease, {Michael Z.} and Chang, {Jenny C.}",
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AU - Dave, Bhuvanesh

AU - Gonzalez, Daniel D.

AU - Liu, Zhi Bin

AU - Li, Xiaoxian

AU - Wong, Helen

AU - Granados, Sergio

AU - Ezzedine, Nadeer E.

AU - Sieglaff, Douglas H.

AU - Ensor, Joe E.

AU - Miller, Kathy

AU - Radovich, Milan

AU - KarinaEtrovic, Agda

AU - Gross, Steven S.

AU - Elemento, Olivier

AU - Mills, Gordon B.

AU - Gilcrease, Michael Z.

AU - Chang, Jenny C.

PY - 2017/6/1

Y1 - 2017/6/1

N2 - 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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