Gata-3 Negatively Regulates the Tumor-Initiating Capacity of Mammary Luminal Progenitor Cells and Targets the Putative Tumor Suppressor Caspase-14
Details
Publication Year 2011-11, Volume 31, Issue #22, Page 4609-4622
Journal Title
MOLECULAR AND CELLULAR BIOLOGY
Publication Type
Journal Article
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.
Publisher
AMER SOC MICROBIOLOGY
Keywords
HUMAN BREAST-TUMORS; GENE-EXPRESSION PROFILES; STEM-CELL; ESTROGEN-RECEPTOR; CANCER MODEL; DIFFERENTIATION; MOUSE; GLAND; TRANSCRIPTOME; TUMORIGENESIS
WEHI Research Division(s)
Molecular Genetics Of Cancer; Bioinformatics
Rights Notice
Copyright © 2011, American Society for Microbiology. All Rights Reserved.


Creation Date: 2011-11-01 12:00:00
Last Modified: 0001-01-01 12:00:00
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