title: Gata-3 negatively regulates the tumor-initiating capacity of mammary luminal progenitor cells and targets the putative tumor suppressor caspase-14.
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.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Marie-Liesse
authors.initials: ML
authors.lastname: Asselin-Labat
authors.forename: Kate D
authors.initials: KD
authors.lastname: Sutherland
authors.forename: François
authors.initials: F
authors.lastname: Vaillant
authors.forename: David E
authors.initials: DE
authors.lastname: Gyorki
authors.forename: Di
authors.initials: D
authors.lastname: Wu
authors.forename: Sheridan
authors.initials: S
authors.lastname: Holroyd
authors.forename: Kelsey
authors.initials: K
authors.lastname: Breslin
authors.forename: Teresa
authors.initials: T
authors.lastname: Ward
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.forename: Mary L
authors.initials: ML
authors.lastname: Bath
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Deb
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Fox
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Smyth
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Lindeman
authors.forename: Jane E
authors.initials: JE
authors.lastname: Visvader
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053456:Caspase 14 / Q000096:biosynthesis / Q000378:metabolism*; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D005260:Female; D050990:GATA3 Transcription Factor / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008321:Mammary Glands, Animal / Q000166:cytology* / Q000378:metabolism; D042361:Mammary Glands, Human / Q000166:cytology* / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008324:Mammary Tumor Virus, Mouse / Q000235:genetics; D051379:Mice; D008875:Middle Aged; D013234:Stem Cells
chemical_list: D000952:Antigens, Polyomavirus Transforming; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D053456:Caspase 14