Gata-3 Negatively Regulates the Tumor-Initiating Capacity of Mammary Luminal Progenitor Cells and Targets the Putative Tumor Suppressor Caspase-14

被引：89

作者：

Asselin-Labat, Marie-Liesse ^{[1
,2
]}

Sutherland, Kate D. ^{[1
]}

Vaillant, Francois ^{[1
,2
]}

Gyorki, David E. ^{[1
,2
]}

Wu, Di ^{[1
,2
]}

Holroyd, Sheridan ^{[1
]}

Breslin, Kelsey ^{[1
]}

Ward, Teresa ^{[1
]}

Shi, Wei ^{[1
,2
]}

Bath, Mary L. ^{[1
]}

Deb, Siddhartha ^{[3
]}

Fox, Stephen B. ^{[3
]}

Smyth, Gordon K. ^{[1
,2
]}

Lindeman, Geoffrey J. ^{[1
,2
,4
]}

Visvader, Jane E. ^{[1
,2
]}

机构：

[1] Walter & Eliza Hall Inst Med Res, Parkville, Vic 3052, Australia

[2] Univ Melbourne, Parkville, Vic 3052, Australia

[3] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia

[4] Royal Melbourne Hosp, Parkville, Vic 3050, Australia

来源：

MOLECULAR AND CELLULAR BIOLOGY | 2011年 / 31卷 / 22期

基金：

澳大利亚国家健康与医学研究理事会; 英国医学研究理事会; 澳大利亚研究理事会;

关键词：

HUMAN BREAST-TUMORS; GENE-EXPRESSION PROFILES; STEM-CELL; ESTROGEN-RECEPTOR; CANCER MODEL; DIFFERENTIATION; MOUSE; GLAND; TRANSCRIPTOME; TUMORIGENESIS;

D O I：

10.1128/MCB.05766-11

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：4609 / 4622

页数：14