GATA-3 and the regulation of the mammary luminal cell fate

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The GATA family of transcription factors plays essential roles in the specification and maintenance of differentiated cell types. GATA-3 was identified in a microarray screen of the mouse mammary gland as the most highly expressed transcription factor in the mammary epithelium and is expressed exclusively in the luminal epithelial cell population. Targeted deletion of GATA-3 in mammary glands leads to profound defects in mammary development and inability to specify and maintain the luminal cell fate in the adult mouse. In breast cancer, GATA-3 has emerged as a strong predictor of tumor differentiation, estrogen-receptor status, and clinical outcome. GATA-3 maintains tumor differentiation and suppresses tumor dissemination in a mouse model of breast cancer. This review explores our current understanding of GATA-3 signaling in luminal cell differentiation, both in mammary development and breast cancer.

Introduction

A central feature of development is the specification, restriction, and maintenance of cell fates from multipotent stem and progenitor cells. From studies in organisms as diverse as sea urchins, flies, and mice, it is becoming clear that the specification of cell fates occurs in part through the activation of gene regulatory networks [1, 2]. These networks are made up of hierarchical sets of transcriptional activators and repressors that activate the effector genes of a given cell fate while repressing the gene products of alternate cell fates. A transcription factor at a given node in the network is activated when a combinatorial set of cis-regulatory elements are bound to its promoter, essentially operating as logic gates in the network [3, 4]. In embryonic stem cells, these transcription factors are normally quiescent but poised for activation as a result of specific patterns of histone methylation and transcriptional repression [5, 6]. The initial specification of cell fate arises in part through juxtacrine and paracrine signaling pathways, such as Wnt and Notch, that activate the initial nodes in the network [1]. These transcription factors then autoactivate in positive-feedback loops and activate the other members in the network in order to establish the differentiated state.

The GATA transcription factors are crucial players in the gene regulatory networks that govern the specification of cell fates. The GATA family is composed of six highly conserved transcription factors that bind the DNA sequence (A/T)GATA(A/G) via two zinc-finger domains with the consensus sequence CX2CX17CX2C [7]. GATA-1, GATA-2, and GATA-3 are linked to the specification of hematopoietic cell fates, while GATA-4, GATA-5, and GATA-6 play crucial roles in the specification of endodermal tissues, including heart and lung. These include the role of GATA-1 in erythropoeisis, GATA-3 in T-cell and Th2 differentiation, GATA-4 in cardiac and gastric epithelial differentiation, and GATA-6 in lung epithelial differentiation [8, 9, 10, 11, 12, 13]. In several systems, GATA factors specify the fate of a specific cell lineage while repressing alternate lineages. For example, GATA-1 and PU.1 transcription factors are necessary for the specification of the erythroid and myeloid lineages, respectively. These factors exhibit transcriptional crossantagonism, in that GATA-1 represses PU.1 by interacting with its cofactor c-Jun, while PU.1 represses GATA-1 DNA-binding activity [12, 14]. This transcriptional crossantagonism reinforces cell fate decisions and commits the cells to their respective fates. In T-helper cells, GATA-3 and T-bet specify the Th2 and Th1 cell fates, respectively [13, 15]. The development of these cell fates depends on the relative levels of these transcription factors, which are reinforced by cell-type-specific cytokines and positive-feedback regulatory loops that autoactivate with cell division [16].

Section snippets

GATA-3 in the mammary gland

The mammary gland is a tubular organ that develops postnatally through branching morphogenesis, whereby a branched ductal network extends into a stromal fat pad to form a branched ductal tree [17]. The structure responsible for the branching process is the terminal end bud (TEB), which consists of epithelial progenitor cells. The differentiated mammary gland is composed of two epithelial cell types, the luminal epithelial and myoepithelial cells. It was recently shown that GATA-3 is necessary

GATA-3 in breast cancer

Breast cancers are luminal epithelial neoplasias that are clinically subdivided on the basis of several tumor markers, including estrogen receptor (ER), progesterone receptor (PR), and HER2/Neu. A series of expression profiling studies of human breast tumors has identified additional tumor markers that predict tumor behavior and clinical outcome. Six independent microarray studies of 369 primary breast tumors found that positive GATA-3 expression is among the best predictors of ER positive

Perspectives

The role of GATA-3 in the differentiation of the mammary luminal cell adds to the growing body of evidence implicating the GATA family of transcription factors as key regulators of cell fate specification and maintenance. GATA-3 promotes the differentiation of luminal cells, while repressing other cell types in the mammary gland, such as adipocytes. The transcription factors that promote the differentiation of myoepithelial cells in the mammary gland have yet to be discovered. Compared to other

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This work was supported by grants from the National Cancer Institute and the National Institute of Environmental Health Sciences (CA056721 and ES012801). HKM was supported by the UCSF Medical Scientist Training Program.

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