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, Tim H.M. Huang, Haifa Shen, Xuewu Liu, Mauro Ferrari, Ming Zhan, Stephen T.C. Wong, Muthiah Kumaraswami, Vivek MittalXi Chen, Steven S. Gross, Jenny C. Chang

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

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

ASJC Scopus subject areas

  • General

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