期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 113, 期 41, 页码 E6107-E6116出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1613417113
关键词
p63; H-Ras; epithelial mesenchymal transition; transcriptional repression; breast cancer
资金
- NIH [P01 CA87497]
- National Science Foundation [ACI-1053575]
- XSEDE
The p53-related transcription factor p63 is required for maintenance of epithelial cell differentiation. We found that activated forms of the Harvey Rat Sarcoma Virus GTPase (H-RAS) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) oncogenes strongly repress expression of Delta Np63 alpha, the predominant p63 isoform in basal mammary epithelial cells. This regulation occurs at the transcriptional level, and a short region of the Delta Np63 promoter is sufficient for repression induced by H-RasV12. The suppression of Delta Np63 alpha expression by these oncogenes concomitantly leads to an epithelial-to-mesenchymal transition (EMT). In addition, the depletion of Delta Np63 alpha alone is sufficient to induce EMT. Both H-RasV12 expression and Delta Np63 alpha depletion induce individual cell invasion in a 3D collagen gel in vitro system, thereby demonstrating how Ras can drive the mammary epithelial cell state toward greater invasive ability. Together, these results suggest a pathway by which RAS and PIK3CA oncogenes induce EMT through regulation of Delta Np63 alpha.
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