ΔNp63 Promotes Stem Cell Activity in Mammary Gland Development and Basal-Like Breast Cancer by Enhancing Fzd7 Expression and Wnt Signalling

Nat Cell Biol. 2014 Oct;16(10):1004-15, 1-13. doi: 10.1038/ncb3040. Epub 2014 Sep 21.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Blotting, Western
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Epithelial Cells / metabolism
  • Frizzled Receptors / genetics
  • Frizzled Receptors / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Interleukin Receptor Common gamma Subunit / deficiency
  • Interleukin Receptor Common gamma Subunit / genetics
  • Mammary Glands, Animal / cytology
  • Mammary Glands, Animal / metabolism
  • Mammary Glands, Human / cytology
  • Mammary Glands, Human / metabolism*
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Mice, Transgenic
  • Microscopy, Confocal
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Oligonucleotide Array Sequence Analysis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stem Cells / cytology
  • Stem Cells / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transplantation, Heterologous
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Wnt Signaling Pathway*

Substances

  • FZD7 protein, human
  • Frizzled Receptors
  • Il2rg protein, mouse
  • Interleukin Receptor Common gamma Subunit
  • TP63 protein, human
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Green Fluorescent Proteins

Associated data

  • GEO/GSE47493