期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 111, 期 24, 页码 8838-8843出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1320769111
关键词
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资金
- National Institutes of Health (NIH)/National Cancer Institute (NCI) [R01 CA138197, U54 CA149196]
- Golfers Against Cancer
- Breast Cancer Research Foundation
- Causes for a Cure
- Team Tiara
- Emily W. Herrman Cancer Research Laboratory
- Komen for Cure KG [081694]
- Fundacion Alfonso Martin Escudero
- Ernest Cockrell Jr. Distinguished Endowed Chair
- US Department of Defense [W81XWH-09-10212, W81XWH-12-1-0414]
- John S. Dunn Research Foundation
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.
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