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- Title
Proapoptotic PUMA targets stem-like breast cancer cells to suppress metastasis.
- Authors
Qi Sun; Lesperance, Jacqueline; Wettersten, Hiromi; Luterstein, Elaine; DeRose, Yoko S.; Welm, Alana; Cheresh, David A.; Desgrosellier, Jay S.; Sun, Qi
- Abstract
Breast cancer cells with stem cell properties are key contributors to metastatic disease, and there remains a need to better understand and target these cells in human cancers. Here, we identified rare stem-like cells in patients' tumors characterized by low levels of the proapoptotic molecule p53-upregulated modulator of apoptosis (PUMA) and showed that these cells play a critical role in tumor progression that is independent of clinical subtype. A signaling axis consisting of the integrin αvβ3, Src kinase, and the transcription factor Slug suppresses PUMA in these cells, promoting tumor stemness. We showed that genetic or pharmacological disruption of αvβ3/Src signaling drives PUMA expression, specifically depleting these stem-like tumor cells; increases their sensitivity to apoptosis; and reduces pulmonary metastasis, with no effect on primary tumor growth. Taken together, these findings point to PUMA as a key vulnerability of stem-like cells and suggest that pharmacological upregulation of PUMA via Src inhibition may represent a strategy to selectively target these cells in a wide spectrum of aggressive breast cancers.
- Subjects
CANCER cells; STEM cells; METASTATIC breast cancer; CANCER invasiveness; HORMONE receptors; PROTEIN metabolism; ANIMAL experimentation; ANTIGENS; BREAST tumors; CELLULAR signal transduction; COMPARATIVE studies; RESEARCH methodology; MEDICAL cooperation; METASTASIS; MICE; PROTEINS; RESEARCH; RESEARCH funding; XENOGRAFTS; EVALUATION research
- Publication
Journal of Clinical Investigation, 2018, Vol 128, Issue 1, p531
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI93707