Targeting RPL39 and MLF2 reduces tumor initiation and metastasis in breast cancer by inhibiting nitric oxide synthase signaling

Bhuvanesh Dave, Sergio Granados-Principal, Rui Zhu, Stephen Benz, Shahrooz Rabizadeh, Patrick Soon-Shiong, Ke Da Yu, Zhimin Shao, Xiaoxian Li, Michael Gilcrease, Zhao Lai, Yidong Chen, Hui-ming Huang, Haifa Shen, Xuewu Liu, Mauro Ferrari, Ming Zhan, Stephen T C Wong, Muthiah Kumaraswami, Vivek Mittal & 3 others Xi Chen, Steven S. Gross, Jenny C. Chang

Research output: Contribution to journalArticle

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Abstract

We previously described a gene signature for breast cancer stem cells (BCSCs) derived from patient biopsies. Selective shRNA knockdown identified ribosomal protein L39 (RPL39) and myeloid leukemia factor 2 (MLF2) as the top candidates that affect BCSC self-renewal. Knock-down of RPL39 and MLF2 by specific siRNA nanoparticles in patient-derived and human cancer xenografts reduced tumor volume and lung metastases with a concomitant decrease in BCSCs. RNA deep sequencing identified damaging mutations in both genes. These mutations were confirmed in patient lung metastases (n = 53) and were statistically associated with shorter median time to pulmonary metastasis. Both genes affect the nitric oxide synthase pathway and are altered by hypoxia. These findings support that extensive tumor heterogeneity exists within primary cancers; distinct subpopulations associated with stem-like properties have increased metastatic potential.

Original languageEnglish (US)
Pages (from-to)8838-8843
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number24
DOIs
StatePublished - 2014

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Myeloid Leukemia
Neoplastic Stem Cells
Nitric Oxide Synthase
Breast Neoplasms
Neoplasm Metastasis
Lung
Small Interfering RNA
Genes
RNA Sequence Analysis
High-Throughput Nucleotide Sequencing
Neoplasms
Mutation
Tumor Burden
Heterografts
Nanoparticles
Biopsy
ribosomal protein L39

ASJC Scopus subject areas

  • General

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Targeting RPL39 and MLF2 reduces tumor initiation and metastasis in breast cancer by inhibiting nitric oxide synthase signaling. / Dave, Bhuvanesh; Granados-Principal, Sergio; Zhu, Rui; Benz, Stephen; Rabizadeh, Shahrooz; Soon-Shiong, Patrick; Yu, Ke Da; Shao, Zhimin; Li, Xiaoxian; Gilcrease, Michael; Lai, Zhao; Chen, Yidong; Huang, Hui-ming; Shen, Haifa; Liu, Xuewu; Ferrari, Mauro; Zhan, Ming; Wong, Stephen T C; Kumaraswami, Muthiah; Mittal, Vivek; Chen, Xi; Gross, Steven S.; Chang, Jenny C.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 24, 2014, p. 8838-8843.

Research output: Contribution to journalArticle

Dave, B, Granados-Principal, S, Zhu, R, Benz, S, Rabizadeh, S, Soon-Shiong, P, Yu, KD, Shao, Z, Li, X, Gilcrease, M, Lai, Z, Chen, Y, Huang, H, Shen, H, Liu, X, Ferrari, M, Zhan, M, Wong, STC, Kumaraswami, M, Mittal, V, Chen, X, Gross, SS & Chang, JC 2014, 'Targeting RPL39 and MLF2 reduces tumor initiation and metastasis in breast cancer by inhibiting nitric oxide synthase signaling', Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 24, pp. 8838-8843. https://doi.org/10.1073/pnas.1320769111
Dave, Bhuvanesh ; Granados-Principal, Sergio ; Zhu, Rui ; Benz, Stephen ; Rabizadeh, Shahrooz ; Soon-Shiong, Patrick ; Yu, Ke Da ; Shao, Zhimin ; Li, Xiaoxian ; Gilcrease, Michael ; Lai, Zhao ; Chen, Yidong ; Huang, Hui-ming ; Shen, Haifa ; Liu, Xuewu ; Ferrari, Mauro ; Zhan, Ming ; Wong, Stephen T C ; Kumaraswami, Muthiah ; Mittal, Vivek ; Chen, Xi ; Gross, Steven S. ; Chang, Jenny C. / Targeting RPL39 and MLF2 reduces tumor initiation and metastasis in breast cancer by inhibiting nitric oxide synthase signaling. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 24. pp. 8838-8843.
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AU - Dave, Bhuvanesh

AU - Granados-Principal, Sergio

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AU - Benz, Stephen

AU - Rabizadeh, Shahrooz

AU - Soon-Shiong, Patrick

AU - Yu, Ke Da

AU - Shao, Zhimin

AU - Li, Xiaoxian

AU - Gilcrease, Michael

AU - Lai, Zhao

AU - Chen, Yidong

AU - Huang, Hui-ming

AU - Shen, Haifa

AU - Liu, Xuewu

AU - Ferrari, Mauro

AU - Zhan, Ming

AU - Wong, Stephen T C

AU - Kumaraswami, Muthiah

AU - Mittal, Vivek

AU - Chen, Xi

AU - Gross, Steven S.

AU - Chang, Jenny C.

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AB - We previously described a gene signature for breast cancer stem cells (BCSCs) derived from patient biopsies. Selective shRNA knockdown identified ribosomal protein L39 (RPL39) and myeloid leukemia factor 2 (MLF2) as the top candidates that affect BCSC self-renewal. Knock-down of RPL39 and MLF2 by specific siRNA nanoparticles in patient-derived and human cancer xenografts reduced tumor volume and lung metastases with a concomitant decrease in BCSCs. RNA deep sequencing identified damaging mutations in both genes. These mutations were confirmed in patient lung metastases (n = 53) and were statistically associated with shorter median time to pulmonary metastasis. Both genes affect the nitric oxide synthase pathway and are altered by hypoxia. These findings support that extensive tumor heterogeneity exists within primary cancers; distinct subpopulations associated with stem-like properties have increased metastatic potential.

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