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

Rumela Chakrabarti; Yong Wei; Julie Hwang; Xiang Hang; Mario Andres Blanco; Abrar Choudhury; Benjamin Tiede; Rose-Anne Romano; Christina DeCoste; Laura Mercatali; Toni Ibrahim; Dino Amadori; Nagarajan Kannan; Connie J Eaves; Satrajit Sinha; Yibin Kang

doi:10.1038/ncb3040

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.

Authors

Affiliations

¹ Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA.
² 1] Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA [2] Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
³ Department of Biochemistry, Center of Excellence in Bioinformatics and Life Sciences, State University of New York at Buffalo, Buffalo, New York 14203, USA.
⁴ Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS, 47014 Meldola, Italy.
⁵ Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada.
⁶ 1] Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA [2] Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA.

PMID: 25241036
PMCID: PMC4183725
DOI: 10.1038/ncb3040

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

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding