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

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. Knockdown 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.

• Authors: 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 Mittal, Xi Chen, Steven S Gross, Jenny C Chang
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 24 Pg. 8838-43 (Jun 17 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 24876273 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• MLF2 protein, human
• Nuclear Proteins
• RNA, Small Interfering
• RPL39L protein, human
• Ribosomal Proteins
• Nitric Oxide
• Nitric Oxide Synthase

Topics

• Animals
• Breast Neoplasms (metabolism, prevention & control)
• Cell Line, Tumor
• Cell Movement
• Female
• Gene Expression Regulation, Neoplastic
• High-Throughput Nucleotide Sequencing
• Humans
• Hypoxia
• Lung Neoplasms (genetics, metabolism)
• Mice
• Mice, SCID
• Mutation
• Neoplasm Metastasis
• Neoplasm Transplantation
• Neoplastic Stem Cells (cytology)
• Nitric Oxide (chemistry)
• Nitric Oxide Synthase (antagonists & inhibitors, metabolism)
• Nuclear Proteins (metabolism)
• RNA, Small Interfering (metabolism)
• Ribosomal Proteins (metabolism)
• Sequence Analysis, RNA
• Signal Transduction
• Time Factors