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ΔNp63 promotes stem cell activity in mammary gland development and basal-like breast cancer by enhancing Fzd7 expression and Wnt signalling

Nature Cell Biology volume 16, pages 10041015 (2014) | Download Citation

Abstract

Emerging evidence suggests that cancer is populated and maintained by tumour-initiating cells (TICs) with stem-like properties similar to those of adult tissue stem cells. Despite recent advances, the molecular regulatory mechanisms that may be shared between normal and malignant stem cells remain poorly understood. Here we show that the ΔNp63 isoform of the Trp63 transcription factor promotes normal mammary stem cell (MaSC) activity by increasing the expression of the Wnt receptor Fzd7, thereby enhancing Wnt signalling. Importantly, Fzd7-dependent enhancement of Wnt signalling by ΔNp63 also governs tumour-initiating activity of the basal subtype of breast cancer. These findings establish ΔNp63 as a key regulator of stem cells in both normal and malignant mammary tissues and provide direct evidence that breast cancer TICs and normal MaSCs share common regulatory mechanisms.

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Acknowledgements

We thank our laboratory members for helpful discussions, R. A. Weinberg and V. Karantza for iMMEC and HMLE cell lines, and A. L. Welm and M. T. Lewis for PDX lines, respectively. This research was supported by grants from the Brewster Foundation, the Department of Defense (BC123187) and the National Institutes of Health (R01CA134519 and R01CA141062) to Y.K. and from the Canadian Cancer Society Research Institute to C.J.E. R.C. and N.K. are recipients of postdoctoral fellowships from the Department of Defense and MITACS, respectively. This research was also supported by the Transgenic/Knockout, Tissue Analytic Service and Flow Cytometry Shared Resources of the Cancer Institute of New Jersey (P30CA072720).

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Affiliations

  1. Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA

    • Rumela Chakrabarti
    • , Yong Wei
    • , Julie Hwang
    • , Xiang Hang
    • , Mario Andres Blanco
    • , Abrar Choudhury
    • , Benjamin Tiede
    • , Christina DeCoste
    •  & Yibin Kang
  2. Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Mario Andres Blanco
  3. Department of Biochemistry, Center of Excellence in Bioinformatics and Life Sciences, State University of New York at Buffalo, Buffalo, New York 14203, USA

    • Rose-Anne Romano
    •  & Satrajit Sinha
  4. Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS, 47014 Meldola, Italy

    • Laura Mercatali
    • , Toni Ibrahim
    •  & Dino Amadori
  5. Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada

    • Nagarajan Kannan
    •  & Connie J. Eaves
  6. Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA

    • Yibin Kang

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Contributions

R.C. and Y.K. designed experiments. R.C., Y.W., J.H., X.H., M.A.B., A.C., B.T., N.K. and S.S. performed the experiments. T.I., L.M., D.A., R-A.R., C.D., N.K. and C.J.E. provided crucial samples and technical advice. R.C. and Y.K. wrote the manuscript. All authors discussed the results and commented on the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Yibin Kang.

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DOI

https://doi.org/10.1038/ncb3040

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