Gata-3 negatively regulates the tumor-initiating capacity of mammary luminal progenitor cells and targets the putative tumor suppressor caspase-14

Marie-Liesse Labat, Kate D. Sutherland, François Vaillant, David E. Gyorki, Di Wu, Sheridan Holroyd, Kelsey Breslin, Teresa Ward, Wei Shi, Mary L. Bath, Siddhartha Deb, Stephen B. Fox, Gordon K. Smyth, Geoffrey J. Lindeman, Jane E. Visvader

Research output: Contribution to journalArticle

75 Scopus citations

Abstract

The transcription factor Gata-3 is a definitive marker of luminal breast cancers and a key regulator of mammary morphogenesis. Here we have explored a role for Gata-3 in tumor initiation and the underlying cellular mechanisms using a mouse model of "luminal-like" cancer. Loss of a single Gata-3 allele markedly accelerated tumor progression in mice carrying the mouse mammary tumor virus promoter-driven polyomavirus middle T antigen (MMTV-PyMT mice), while overexpression of Gata-3 curtailed tumorigenesis. Through the identification of two distinct luminal progenitor cells in the mammary gland, we demonstrate that Gata-3 haplo-insufficiency increases the tumor-initiating capacity of these progenitors but not the stem cell-enriched population. Overexpression of a conditional Gata-3 transgene in the PyMT model promoted cellular differentiation and led to reduced tumor-initiating capacity as well as diminished angiogenesis. Transcript profiling studies identified caspase-14 as a novel downstream target of Gata-3, in keeping with its roles in differentiation and tumorigenesis. A strong association was evident between GATA-3 and caspase-14 expression in preinvasive ductal carcinoma in situ samples, where GATA-3 also displayed prognostic significance. Overall, these studies identify GATA-3 as an important regulator of tumor initiation through its ability to promote the differentiation of committed luminal progenitor cells.

Original languageEnglish (US)
Pages (from-to)4609-4622
Number of pages14
JournalMolecular and Cellular Biology
Volume31
Issue number22
DOIs
Publication statusPublished - Nov 1 2011
Externally publishedYes

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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