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PMID: 19225568 Published · ppublish English Comparative Study Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

MMTV-Wnt1 and -DeltaN89beta-catenin induce canonical signaling in distinct progenitors and differentially activate Hedgehog signaling within mammary tumors.

PloS one ·Vol. 4 ·No. 2 ·2009-00-00 ·Pages e4537

Teissedre B, Pinderhughes A, Incassati A, Hatsell SJ, Hiremath M, Cowin P

Abstract

Canonical Wnt/beta-catenin signaling regulates stem/progenitor cells and, when perturbed, induces many human cancers. A significant proportion of human breast cancer is associated with loss of secreted Wnt antagonists and mice expressing MMTV-Wnt1 and MMTV-DeltaN89beta-catenin develop mammary adenocarcinomas. Many studies have assumed these mouse models of breast cancer to be equivalent. Here we show that MMTV-Wnt1 and MMTV-DeltaN89beta-catenin transgenes induce tumors with different phenotypes. Using axin2/conductin reporter genes we show that MMTV-Wnt1 and MMTV-DeltaN89beta-catenin activate canonical Wnt signaling within distinct cell-types. DeltaN89beta-catenin activated signaling within a luminal subpopulation scattered along ducts that exhibited a K18(+)ER(-)PR(-)CD24(high)CD49f(low) profile and progenitor properties. In contrast, MMTV-Wnt1 induced canonical signaling in K14(+) basal cells with CD24/CD49f profiles characteristic of two distinct stem/progenitor cell-types. MMTV-Wnt1 produced additional profound effects on multiple cell-types that correlated with focal activation of the Hedgehog pathway. We document that large melanocytic nevi are a hitherto unreported hallmark of early hyperplastic Wnt1 glands. These nevi formed along the primary mammary ducts and were associated with Hedgehog pathway activity within a subset of melanocytes and surrounding stroma. Hh pathway activity also occurred within tumor-associated stromal and K14(+)/p63(+) subpopulations in a manner correlated with Wnt1 tumor onset. These data show MMTV-Wnt1 and MMTV-DeltaN89beta-catenin induce canonical signaling in distinct progenitors and that Hedgehog pathway activation is linked to melanocytic nevi and mammary tumor onset arising from excess Wnt1 ligand. They further suggest that Hedgehog pathway activation maybe a critical component and useful indicator of breast tumors arising from unopposed Wnt1 ligand.

MeSH Terms
Animals Hedgehog Proteins/metabolism Mammary Neoplasms, Animal/etiology,pathology Mammary Tumor Virus, Mouse/chemistry,metabolism Mice Neoplastic Stem Cells/pathology Signal Transduction Wnt1 Protein/physiology beta Catenin/physiology
Chemicals
Hedgehog Proteins Wnt1 Protein Wnt1 protein, mouse beta Catenin
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Teissedre Brigitte
Departments of Cell Biology and Dermatology, New York University School of Medicine, New York, New York, United States of America.
Pinderhughes Alicia
Incassati Angela
Hatsell Sarah J
Hiremath Minoti
Cowin Pamela
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Article Info
Journal
PloS one
Abbr.
PLoS One
ISSN
1932-6203
DOI
10.1371/journal.pone.0004537
Published
2009-00-00
Epub
2009-00-19
Pages
e4537
Language
English
Region
United States
NLM ID
101285081
PMCID
PMC2639708
Subset
IM
Grants
NCI NIH HHS · F31CA130137 · United States
NIGMS NIH HHS · R01 GM047429 · United States
NIGMS NIH HHS · NIH-R01-GM47429 · United States
NCI NIH HHS · NIH-R21-CA129905 · United States
NCI NIH HHS · F31 CA130137 · United States
NCI NIH HHS · F31 CA119940 · United States
NCI NIH HHS · F31CA119940-02 · United States
Corrections
ErratumIn
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External Links
PubMed source DOI: 10.1371/journal.pone.0004537 PMC Full Text View journal details
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