Gata-3 Negatively Regulates the Tumor-Initiating Capacity of Mammary Luminal Progenitor Cells and Targets the Putative Tumor Suppressor Caspase-14
- Author(s)
- Asselin-Labat, ML; Sutherland, KD; Vaillant, F; Gyorki, DE; Wu, D; Holroyd, S; Breslin, K; Ward, T; Shi, W; Bath, ML; Deb, S; Fox, SB; Smyth, GK; Lindeman, GJ; Visvader, JE;
- 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
- Research Division(s)
- Molecular Genetics Of Cancer; Bioinformatics
- Publisher's Version
- https://doi.org/10.1128/MCB.05766-11
- Open Access at Publisher's Site
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3209243/- Terms of Use/Rights Notice
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Creation Date: 2011-11-01 12:00:00