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MMTV-Wnt1 and -DN89b-Catenin Induce Canonical Signaling in Distinct Progenitors and Differentially Activate Hedgehog Signaling within Mammary Tumors
PLoS ONE (2009)
  • Brigitte Teissedre
  • Alicia Pinderhughes
  • Angela Incassati
  • Sarah J. Hatsell
  • Minoti Hiremath
  • Pamela Cowin
Abstract

Canonical Wnt/b-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 MMTVWnt1 and MMTV-DN89b-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-DN89b-catenin transgenes induce tumors with different phenotypes. Using axin2/conductin reporter genes we show that MMTV-Wnt1 and MMTV-DN89b-catenin activate canonical Wnt signaling within distinct cell-types. DN89b-catenin activated signaling within a luminal subpopulation scattered along ducts that exhibited a K18+ER2PR2CD24highCD49flow 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.MMTVWnt1 produced additional profound effects on multiple cell-types that correlated with focal activation of the Hedgehog pathway. We document that largemelanocytic nevi are a hitherto unreported hallmark of early hyperplasticWnt1 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-DN89b-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.

Publication Date
February 19, 2009
Publisher Statement
This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Citation Information
Brigitte Teissedre, Alicia Pinderhughes, Angela Incassati, Sarah J. Hatsell, et al.. "MMTV-Wnt1 and -DN89b-Catenin Induce Canonical Signaling in Distinct Progenitors and Differentially Activate Hedgehog Signaling within Mammary Tumors" PLoS ONE Vol. 4 Iss. 2 (2009)
Available at: http://works.bepress.com/minoti_hiremath/4/