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Proapoptotic PUMA targets stem-like breast cancer cells to suppress metastasis
Qi Sun, … , David A. Cheresh, Jay S. Desgrosellier
Qi Sun, … , David A. Cheresh, Jay S. Desgrosellier
Published December 11, 2017
Citation Information: J Clin Invest. 2018;128(1):531-544. https://doi.org/10.1172/JCI93707.
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Research Article Oncology Stem cells

Proapoptotic PUMA targets stem-like breast cancer cells to suppress metastasis

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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.

Authors

Qi Sun, Jacqueline Lesperance, Hiromi Wettersten, Elaine Luterstein, Yoko S. DeRose, Alana Welm, David A. Cheresh, Jay S. Desgrosellier

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Figure 2

Coexpression of αvβ3 and Slug reveals unique stem-like cells in a broad-spectrum of clinical subtypes but does not impact EMT.

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Coexpression of αvβ3 and Slug reveals unique stem-like cells in a broad-...
(A and B) Representative images of immunohistochemical staining for β3 (blue) and Slug (brown) in breast cancer samples from patient-derived xenografts (A and B, bottom) and tissue microarrays (B, top). (A) Shown is a tumor with heterogeneous staining for β3 and Slug. n = 5/30, β3+Slug+ tumors/total. Scale bars: 40 μm and 10 μm (enlarged insets). (B) β3+Slug+ cells (arrows) are shown for ER– and ER+ tumors (top) as well as tumors representing different intrinsic molecular subtypes (bottom). (B, top) n = 19/125, β3+Slug+ tumors/total: n = 10, ER+; n = 4, HER2+; n = 5, triple-negative (TN). (B, bottom) n = 4/12, β3+Slug+ tumors/total: n = 2, luminal B; n = 2, basal-like. Scale bars: 20 μm. (C) Frequency of β3+Slug+ cells in immunohistochemically stained “baseline” breast cancer samples from recurrence-free patients and patients who later progressed to form distant recurrences. Numbers above each bar indicate the number of β3+Slug+ tumors per total number of tumors. P = 0.0068 (ER–) and P = 0.0329 (ER+), for no recurrence versus distant recurrence. *P < 0.05 and **P < 0.01. Statistical analysis was performed by Fisher’s exact test. (D–G) Western blot analysis for the indicated proteins in a panel of breast cancer cell lines representing distinct subtypes (D), BT549 cells stably expressing β3 shRNA (shβ3) or a nonsilencing control shRNA (shCtrl) (E and G), or BT474 cells expressing ectopic β3 cDNA (β3) or a vector-only control (Ctrl) (F and G). For all immunoblots, data shown are representative of 3 independent experiments, and β-actin was used as a loading control. (H) Representative immunofluorescence images showing vimentin (red) and E-cadherin (green) in LM2-4 and MCF7 cells, with or without β3. Nuclei are stained blue in all panels. Scale bars: 20 μm. See also Supplemental Figures 2 and 3.
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