Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Curr Opin Cell Biol. Author manuscript; available in PMC 2009 Apr 1.
Published in final edited form as:
PMCID: PMC2397451

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


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 and independent 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.


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 critical 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 critical 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 [8-13]. 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 cross-antagonism, in that GATA-1 represses PU.1 by interacting with its co-factor c-Jun, while PU.1 represses GATA-1 DNA-binding activity [12,14]. This transcriptional cross-antagonism reinforces cell fate decisions and commits the cells to their respective fates. In T-helper cells, GATA-3 and T-bet specify the Th-2 and Th-1 cell fates, respectively [13,15]. The development of these cell fates depend on the relative levels of these transcription factors, which are reinforced by cell-type specific cytokines and positive-feedback regulatory loops that auto-activate with cell division [16].

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 for the specification and maintenance of the luminal cell fate [18••,19••]. In a microarray screen in which the gene expression profile of pubertal mammary epithelium was compared to epithelium-free stroma, GATA-3 emerged as the most highly enriched transcription factor in the mammary epithelium [18••,20•]. GATA-3 protein was restricted to the luminal cells and was absent in myoepithelial cells. The targeted loss of GATA-3 via MMTV-Cre mediated deletion of floxed-GATA-3 led to profound defects in mammary branching morphogenesis due to the failure of TEB formation, indicating that GATA-3 is necessary for mammary development. Further, the inducible deletion of GATA-3 in adult mammary glands using Cre/lox recombination led to the proliferation of luminal cells with loss of differentiation markers, such as E-cadherin and β-casein. The GATA-3 null cells ultimately detached from the basement membrane and underwent caspase-mediated cell death in the ductal lumen, indicating that GATA-3 is necessary to maintain luminal cell differentiation in the adult mammary gland. As a result, GATA-3 null mammary glands showed profound defects in lobulo-alveolar development and significantly decreased milk protein expression and lactation [18••,19••].

With the in vivo importance of GATA-3 established, it was then shown that GATA-3 is necessary for the specification of luminal cells from mammary stem/progenitor cells. The cell surface markers CD24, CD29, and CD61 enrich for mammary stem cells and luminal progenitor cells [21,22]. The targeted deletion of GATA-3 in mammary glands led to a profound expansion in the progenitor population, indicating that luminal cell differentiation is blocked in the absence of GATA-3. The retroviral introduction of GATA-3 in mammary stem cells was sufficient to induce markers of luminal differentiation, including whey acidic protein and β-casein [19••]. This indicated that GATA-3 is necessary and sufficient for luminal cell specification (Figure 1A). To uncover additional transcription factors that may cooperate with GATA-3 in its gene regulatory network, data mining was performed on the mammary epithelial microarray data set. This yielded several epithelial-specific transcription factors, including FOXA1, MSX2, FOXP4, TRPS1, ELF5, EHF, RUNX1, and members of the Id, Irx, Sox, and TCFAP-2 transcription factor families [18••]. Of these, FOXA1 showed a strong positive correlation with GATA-3 in four independent human breast cancer microarray datasets, suggesting that GATA-3 and FOXA1 may be coordinately regulated. Indeed, promoter analysis and chromatin immunoprecipitation indicated that FOXA1 contained a functional GATA-3 binding site, which suggests that FOXA1 may a downstream effector of GATA-3 signaling [18••] (Figure 1B). Other work showed that GATA-3 represses adipocyte differentiation by inhibiting PPARγ [23•]. Thus, in addition to activating luminal cell genes, GATA-3 likely represses the gene products of non-luminal cell types in the mammary gland (Figure 1B).

Figure 1
(A) Schematic representation of the role of GATA-3 in specifying and maintaining the luminal cell fate in the mammary gland.

Other transcription factors that are necessary for mammary development and luminal cell differentiation may similarly cooperate with GATA-3 in its gene regulatory network. The homeobox genes Msx1 and Msx2 are co-expressed in the post-natal mammary epithelium, and deficiency of Msx2 leads to arrest in mammary sprouting at E16.5, similar to the mammary phenotype of conditional GATA-3 null mice [24,25]. The Friend of GATA (FOG) transcriptional effectors are multi-zinc finger proteins that bind to the N-terminal zinc finger of GATA factors and regulate their activity [26]. FOG-1 and FOG-2 are necessary for the functions of GATA-1 and GATA-4 during erythropoeisis and cardiac morphogenesis, respectively [26,27]. FOG-1 affects the temporal and transcriptional activity of GATA-1, making it a key regulator of GATA-1 in the erythroid gene regulatory network [28]. In the mammary gland, FOG-2 is upregulated during pregnancy and lactation. The mammary-specific deletion of FOG-2 using WAP-Cre led to accelerated involution of the lactating mammary gland, suggesting that the GATA-3/FOG-2 interaction may be necessary for lobulo-alveolar development [29]. The upregulation of FOG-2 during pregnancy may modify the transcriptional activity of GATA-3 in luminal cells, thereby modifying effector gene activation during lobulo-alveolar development (Figure 1B). Other transcriptional regulators are upregulated in the lactating mammary gland and are necessary for lobulo-alveolar development, including C/EBPβ, Id2, Stat5a, HoxA9, HoxB9, and HoxD9 [30]. Further work will be necessary to define the interactions between GATA-3 and these transcriptional regulators and to further characterize the GATA-3 gene regulatory network in the mammary gland.

A fundamental topic to be explored is the mechanism by which GATA-3 is activated during the luminal cell specification. In other systems, Notch and Wnt are critical mediators of cell fate decisions and activators of GATA expression. The development of endomesoderm in sea urchins arises through the activation of the Wnt-8/Frizzled/β-catenin pathway in veg2 endomesodermal progenitor cells. The Wnt pathway activates three transcription factors, including a GATA factor (gatae), which autoactivate in positive-feedback loops and then repress Wnt8, making the Wnt pathway a transient specification signal for veg2 cells [1]. In T helper cells, Notch signaling is necessary for the induction of GATA-3 expression and the differentiation of Th2 cells. Notch directly binds to the GATA-3 promoter and synergizes with GATA-3 to promote Th2 effector gene expression [31,32]. In the mammary gland, a role for canonical Wnt signaling has been implicated in mammary epithelial specification. Canonical Wnt signaling is present in mesenchymal cells at 12.5 dpc during the early stages of mammary placode formation and subsequently appears in the developing epithelial buds between 12.5 and 15.5 dpc [33]. Mice deficient in Lef1, a member of the Lef/Tcf family of canonical β-catenin signaling effectors, have a significantly reduced ability to form mammary epithelial placodes [33,34]. Further work is needed to determine if GATA-3 lies downstream of Wnt signaling in this process and which Wnt factors are responsible for placode formation. Candidate Wnt factors include Wnt-2, Wnt-5a, and Wnt-7b, which are enriched in mammary terminal end buds, while Wnt-4, Wnt-5b, and Wnt-6 are expressed throughout the mammary epithelium [20•,35].

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 have 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 status [36•-41•]. In two studies, artificial neural network and correlative gene analysis identified GATA-3 as the third best and best predictor of ER status, respectively [36•,40•]. Additional microarray studies showed that human breast cancers can be classified into five distinct sub-groups, including the Luminal A, Luminal B, ERBB2, basal-like, and normal breast sub-classes [41•-43•]. In these studies, GATA-3 expression was strongly correlated with the Luminal A sub-type of breast tumors, which expressed luminal differentiation markers and carried the best prognostic outcome among the sub-classes. Meta-analysis of four microarray datasets indicated that GATA-3 was a strong predictor of clinical outcome in breast tumors, with independent prognostic significance above conventional variables [44••]. Low GATA-3 expression was strongly predictive of poor clinical outcome, high tumor grade, positive lymph node status, and large tumor size. Log-rank analysis of a microarray dataset revealed that GATA-3 expression was the second best predictor of clinical outcome among 8024 genes, with its low expression indicating a poor prognosis [45•]. Additionally, two tissue microarray studies of 389 primary breast tumors showed that GATA-3 status carried strong prognostic significance in breast cancer [44••,46]. Rare functional mutations of GATA-3 have also been reported in primary breast tumors [47]. These studies have implicated a role for GATA-3 in breast cancer biology and prognosis, but functional studies that define that role are lacking.

Using the MMTV-PyMT mouse model of breast cancer, we have investigated the role of GATA-3 in breast cancer pathogenesis and progression [48••]. MMTV-PyMT mice develop luminal breast cancers that progress from hyperplasias to carcinomas, which reliably model human breast cancer [49,50]. We isolated focal, GFP-positive hyperplasias from a 3-week-old MMTV-PyMT mouse and transplanted them into wild-type mice to follow tumor progression. Between 5 and 8 weeks post-transplant, tumor outgrowths displayed histologic progression from adenoma to carcinoma and onset of tumor dissemination to distant sites. Between 15 and 18 weeks post-transplant the outgrowths progressed to late carcinoma and acquired metastatic capability. This model allowed the separation of the processes of tumor dissemination and metastasis and allowed the dissection of the individual steps during malignant progression.

Microarray analysis revealed that loss of luminal differentiation genes highly correlated with tumor progression in the model. Among these genes, GATA-3 expression was lost early in tumor progression during the transition from adenoma to early carcinoma and the onset of tumor dissemination. The retroviral restoration of GATA-3 in late carcinomas was sufficient to induce luminal differentiation markers, such as β-casein [48••], similar to observations in mammary epithelial cells and cell lines [19••,47]. The GATA-3-infected tumors showed a significantly reduced ability to disseminate to distant sites. Significantly, the inducible deletion of GATA-3 in well-differentiated tumors led to caspase-mediated cell death, suggesting that loss of GATA-3 is not sufficient to promote malignant progression. Instead, a GATA-3 negative stem cell-like tumor cell population persisting in early tumors expanded during tumor progression and was responsible for the transition to the GATA-3 negative state. These data indicate that GATA-3 is a critical regulator of tumor differentiation and suppressor of tumor dissemination and that its lack of expression underlies the early stages of breast cancer progression.

A central question to be addressed is how GATA-3 and ER cooperate in mammary development and breast cancer. Though GATA-3 and ER are strongly correlated in breast cancers, ER is expressed in 40-50 percent of luminal cells and in fibroblasts and other stromal cells of the mammary gland [51]. Estradiol stimulation of mammary epithelial cells is not sufficient to induce GATA-3, suggesting that GATA-3 is not a downstream target of ER [39•]. However, GATA-3 is necessary for ERα signaling in the T47D cell line [52]. The targeted deletion of ER in mice led to the inability to form TEBs, similar to the GATA-3 conditional knockout mice. However, luminal differentiation genes were still expressed in the absence of ERα [53]. Further, ER activity induces cellular proliferation, while GATA factors are implicated in cellular quiescence [18••,54,55]. It appears that the GATA-3 and ER pathways may have non-overlapping functions in mammary luminal cells, and these functions may be functionally linked by transcriptional regulators. A candidate linker is FOXA1, which is necessary for the transcriptional activity of ERα and its binding to estrogen response elements in target gene promoters [56,57]. As FOXA1 may also be a downstream effector of GATA-3, FOXA1 may be a bridge between the GATA-3 and ER pathways [18••] (Figure 1B). Further work will be necessary to define the interactions between these transcriptional regulators and to delineate their roles in the gene regulatory network of the luminal cell.


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 systems, the mammary gland offers several advantages for the further study of these processes, including the simplicity of the organ, the presence of only two epithelial cell types, and the ease of experimental manipulation. Understanding how GATA-3 regulates luminal cell differentiation will shed further light on its role in breast cancer, where its importance as a prognostic factor and predictor of tumor grade and differentiation status has been underscored by a multitude of gene expression profiling studies. GATA-3 defines a distinct class of cancer related genes that are differentiation factors, rather than conventional tumor suppressor genes. It maintains the differentiated state in the pre-cancerous state and its activation enforces differentiation into a luminal cell fate, reversing the malignant phenotype. Uncovering the paracrine or juxtacrine signals that activate GATA-3 during luminal cell specification may offer therapeutic strategies for inducing GATA-3 and cellular differentiation in mammary adenocarcinomas. The prospect of a differentiation therapy of breast cancer awaits further mechanistic understanding of GATA-3 in mammary luminal cells.


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


Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References and recommended reading

Papers of particular interest have been highlighted as:

• of special interest

•• of outstanding interest

1. Davidson EH, Rast JP, Oliveri P, Ransick A, Calestani C, Yuh CH, Minokawa T, Amore G, Hinman V, Arenas-Mena C, et al. A genomic regulatory network for development. Science. 2002;295:1669–1678. [PubMed]
2. Davidson EH, Erwin DH. Gene regulatory networks and the evolution of animal body plans. Science. 2006;311:796–800. [PubMed]
3. Singh H, Medina KL, Pongubala JM. Contingent gene regulatory networks and B cell fate specification. Proc Natl Acad Sci U S A. 2005;102:4949–4953. [PMC free article] [PubMed]
4. Swiers G, Patient R, Loose M. Genetic regulatory networks programming hematopoietic stem cells and erythroid lineage specification. Dev Biol. 2006;294:525–540. [PubMed]
5. Lee TI, Jenner RG, Boyer LA, Guenther MG, Levine SS, Kumar RM, Chevalier B, Johnstone SE, Cole MF, Isono K, et al. Control of developmental regulators by Polycomb in human embryonic stem cells. Cell. 2006;125:301–313. [PMC free article] [PubMed]
6. Bernstein BE, Mikkelsen TS, Xie X, Kamal M, Huebert DJ, Cuff J, Fry B, Meissner A, Wernig M, Plath K, et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell. 2006;125:315–326. [PubMed]
7. Patient RK, McGhee JD. The GATA family (vertebrates and invertebrates) Curr Opin Genet Dev. 2002;12:416–422. [PubMed]
8. Jacobsen CM, Narita N, Bielinska M, Syder AJ, Gordon JI, Wilson DB. Genetic mosaic analysis reveals that GATA-4 is required for proper differentiation of mouse gastric epithelium. Dev Biol. 2002;241:34–46. [PubMed]
9. Keijzer R, van Tuyl M, Meijers C, Post M, Tibboel D, Grosveld F, Koutsourakis M. The transcription factor GATA6 is essential for branching morphogenesis and epithelial cell differentiation during fetal pulmonary development. Development. 2001;128:503–511. [PubMed]
10. Kuo CT, Morrisey EE, Anandappa R, Sigrist K, Lu MM, Parmacek MS, Soudais C, Leiden JM. GATA4 transcription factor is required for ventral morphogenesis and heart tube formation. Genes Dev. 1997;11:1048–1060. [PubMed]
11. Yang H, Lu MM, Zhang L, Whitsett JA, Morrisey EE. GATA6 regulates differentiation of distal lung epithelium. Development. 2002;129:2233–2246. [PubMed]
12. Lowry JA, Mackay JP. GATA-1: one protein, many partners. Int J Biochem Cell Biol. 2006;38:6–11. [PubMed]
13. Ho IC, Pai SY. GATA-3 - not just for Th2 cells anymore. Cell Mol Immunol. 2007;4:15–29. [PubMed]
14. Galloway JL, Wingert RA, Thisse C, Thisse B, Zon LI. Loss of gata1 but not gata2 converts erythropoiesis to myelopoiesis in zebrafish embryos. Dev Cell. 2005;8:109–116. [PubMed]
15. Zheng W, Flavell RA. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell. 1997;89:587–596. [PubMed]
16. Grogan JL, Locksley RM. T helper cell differentiation: on again, off again. Curr Opin Immunol. 2002;14:366–372. [PubMed]
17. Sternlicht MD, Kouros-Mehr H, Lu P, Werb Z. Hormonal and local control of mammary branching morphogenesis. Differentiation. 2006;74:365–381. [PMC free article] [PubMed]
•• 18. Kouros-Mehr H, Slorach EM, Sternlicht MD, Werb Z. GATA-3 maintains the differentiation of the luminal cell fate in the mammary gland. Cell. 2006;127:1041–1055. [PMC free article] [PubMed]In this report, GATA-3 is identified in a microarray screen as the most highly expressed transcription factor in the mouse mammary epithelium. The targeted deletion of GATA-3 in mouse mammary glands is described using MMTV-Cre and tet-inducible WAP-rtTA-Cre excision of floxed GATA-3. GATA-3 is shown to be necessary for mammary development and for maintenance of luminal cell differentiation in the adult mammary gland. Further, a transcriptional link between GATA-3 and FOXA1 is described.
•• 19. Asselin-Labat ML, Sutherland KD, Barker H, Thomas R, Shackleton M, Forrest NC, Hartley L, Robb L, Grosveld FG, van der Wees J, et al. Gata-3 is an essential regulator of mammary-gland morphogenesis and luminal-cell differentiation. Nat Cell Biol. 2007;9:201–209. [PubMed]The targeted deletion of GATA-3 in mouse mammary glands using MMTV-Cre and WAP-Cre is described, indicating that GATA-3 is necessary for mammary development and lactation. Further, mammary stem cells were isolated using the cell surface markers CD24, CD29, and CD61 and deficiency of GATA-3 prevented their differentiation into mature luminal cells. Restoration of GATA-3 in mammary stem cells was sufficient to induce markers of luminal differentiation.
• 20. Kouros-Mehr H, Werb Z. Candidate regulators of mammary branching morphogenesis identified by genome-wide transcript analysis. Dev Dyn. 2006;235:3404–3412. [PMC free article] [PubMed]A microarray screen of the developing mouse mammary gland in which GATA-3 was identified as the most enriched transcription factor in the mammary epithelium [18]. The expression profiles of terminal end bud and mature duct microenvironments were compared to epithelium-free stroma. Transcription factors and Wnt, hedgehog and ephrin family members were identified in terminal end buds.
21. Stingl J, Eirew P, Ricketson I, Shackleton M, Vaillant F, Choi D, Li HI, Eaves CJ. Purification and unique properties of mammary epithelial stem cells. Nature. 2006;439:993–997. [PubMed]
22. Shackleton M, Vaillant F, Simpson KJ, Stingl J, Smyth GK, Asselin-Labat ML, Wu L, Lindeman GJ, Visvader JE. Generation of a functional mammary gland from a single stem cell. Nature. 2006;439:84–88. [PubMed]
• 23. Tong Q, Dalgin G, Xu H, Ting CN, Leiden JM, Hotamisligil GS. Function of GATA transcription factors in preadipocyte-adipocyte transition. Science. 2000;290:134–138. [PubMed]The authors show that GATA-3 represses adipocyte differentiation through its negative regulation of PPARγ. Enforced retroviral expression of GATA-3 in a preadipocyte cell line blocked adipocyte differentiation, and GATA-3 null mice exhibited increased adipogenesis.
24. Satokata I, Ma L, Ohshima H, Bei M, Woo I, Nishizawa K, Maeda T, Takano Y, Uchiyama M, Heaney S, et al. Msx2 deficiency in mice causes pleiotropic defects in bone growth and ectodermal organ formation. Nat Genet. 2000;24:391–395. [PubMed]
25. Phippard DJ, Weber-Hall SJ, Sharpe PT, Naylor MS, Jayatalake H, Maas R, Woo I, Roberts-Clark D, Francis-West PH, Liu YH, et al. Regulation of Msx-1, Msx-2, Bmp-2 and Bmp-4 during foetal and postnatal mammary gland development. Development. 1996;122:2729–2737. [PubMed]
26. Cantor AB, Orkin SH. Coregulation of GATA factors by the Friend of GATA (FOG) family of multitype zinc finger proteins. Semin Cell Dev Biol. 2005;16:117–128. [PubMed]
27. Tevosian SG, Deconinck AE, Tanaka M, Schinke M, Litovsky SH, Izumo S, Fujiwara Y, Orkin SH. FOG-2, a cofactor for GATA transcription factors, is essential for heart morphogenesis and development of coronary vessels from epicardium. Cell. 2000;101:729–739. [PubMed]
28. Bresnick EH, Martowicz ML, Pal S, Johnson KD. Developmental control via GATA factor interplay at chromatin domains. J Cell Physiol. 2005;205:1–9. [PubMed]
29. Manuylov NL, Smagulova FO, Tevosian SG. Fog2 excision in mice leads to premature mammary gland involution and reduced Esr1 gene expression. Oncogene. 2007;26:5204–5213. [PubMed]
30. Visvader JE, Lindeman GJ. Transcriptional regulators in mammary gland development and cancer. Int J Biochem Cell Biol. 2003;35:1034–1051. [PubMed]
31. Fang TC, Yashiro-Ohtani Y, Del Bianco C, Knoblock DM, Blacklow SC, Pear WS. Notch directly regulates Gata3 expression during T helper 2 cell differentiation. Immunity. 2007;27:100–110. [PMC free article] [PubMed]
32. Amsen D, Antov A, Jankovic D, Sher A, Radtke F, Souabni A, Busslinger M, McCright B, Gridley T, Flavell RA. Direct regulation of Gata3 expression determines the T helper differentiation potential of Notch. Immunity. 2007;27:89–99. [PMC free article] [PubMed]
33. van Genderen C, Okamura RM, Farinas I, Quo RG, Parslow TG, Bruhn L, Grosschedl R. Development of several organs that require inductive epithelial-mesenchymal interactions is impaired in LEF-1-deficient mice. Genes Dev. 1994;8:2691–2703. [PubMed]
34. Boras-Granic K, Chang H, Grosschedl R, Hamel PA. Lef1 is required for the transition of Wnt signaling from mesenchymal to epithelial cells in the mouse embryonic mammary gland. Dev Biol. 2006;295:219–231. [PubMed]
35. Weber-Hall SJ, Phippard DJ, Niemeyer CC, Dale TC. Developmental and hormonal regulation of Wnt gene expression in the mouse mammary gland. Differentiation. 1994;57:205–214. [PubMed]
• 36. Bertucci F, Houlgatte R, Benziane A, Granjeaud S, Adelaide J, Tagett R, Loriod B, Jacquemier J, Viens P, Jordan B, et al. Gene expression profiling of primary breast carcinomas using arrays of candidate genes. Hum Mol Genet. 2000;9:2981–2991. [PubMed]Expression profiling of 34 breast tumors using 176 gene cDNA microarrays identifies GATA-3 as the best predictor of estrogen receptor status and lymph node status. GATA-3 was also among the best predictors of clinical outcome.
• 37. West M, Blanchette C, Dressman H, Huang E, Ishida S, Spang R, Zuzan H, Olson JA, Jr, Marks JR, Nevins JR. Predicting the clinical status of human breast cancer by using gene expression profiles. Proc Natl Acad Sci U S A. 2001;98:11462–11467. [PMC free article] [PubMed]Expression profiling of 49 breast tumors with Affymetrix microarrays identified GATA-3 as the 9th best predictor of estrogen receptor status among all genes.
• 38. van 't Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, Peterse HL, van der Kooy K, Marton MJ, Witteveen AT, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002;415:530–536. [PubMed]Expression profiling of 117 breast tumors using long-oligonucleotide spotted microarrays with 25,000 features found strong correlation between GATA-3 expression and estrogen-receptor positive status.
• 39. Hoch RV, Thompson DA, Baker RJ, Weigel RJ. GATA-3 is expressed in association with estrogen receptor in breast cancer. Int J Cancer. 1999;84:122–128. [PubMed]Expression profiling of MCF-7, T47D, MDA-MB-231, and HBL-100 cell lines revealed strong positive correlation between GATA-3 and ER expression. Immunostaining of 47 primary breast tumors with ERα and GATA-3 antibodies confirms this association. Estradiol stimulation of breast cancer cell lines did not induce GATA-3 expression.
•40. Gruvberger S, Ringner M, Chen Y, Panavally S, Saal LH, Borg A, Ferno M, Peterson C, Meltzer PS. Estrogen receptor status in breast cancer is associated with remarkably distinct gene expression patterns. Cancer Res. 2001;61:5979–5984. [PubMed]Expression profiling and artifical neural network analysis of 58 breast tumors using 6700 gene cDNA microarrays identified GATA-3 as the 3rd best predictor of ER status.
• 41. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, et al. Molecular portraits of human breast tumours. Nature. 2000;406:747–752. [PubMed]Using expression profiling of 65 breast tumors from 42 individuals using 8100 gene cDNA microarrays, the authors show that breast cancers can be divided into at least 4 sub-types. GATA-3 was strongly associated with the luminal sub-type of breast cancer, which carried the best prognosis among the sub-types.
• 42. Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Johnsen H, Pesich R, Geisler S, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci U S A. 2003;100:8418–8423. [PMC free article] [PubMed]The authors analyze microarray data from three studies with 281 breast tumors and show that breast cancers can be divided into five sub-types. GATA-3 strongly correlated with the Luminal A sub-type, which had the best prognosis among the groups. GATA-3 was down-regulated in the erbB2 and basal-like tumors, which carried the worst prognosis.
• 43. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. 2001;98:10869–10874. [PMC free article] [PubMed]Expression profiling of 85 breast tumors, fibroadenomas and normal breast samples with 8100 gene cDNA arrays sub-divided breast cancers into 5 sub-groups, with GATA-3 strongly correlating with the Luminal A sub-type of breast cancer.
•• 44. Mehra R, Varambally S, Ding L, Shen R, Sabel MS, Ghosh D, Chinnaiyan AM, Kleer CG. Identification of GATA3 as a breast cancer prognostic marker by global gene expression meta-analysis. Cancer Res. 2005;65:11259–11264. [PubMed]A meta-analysis of expression profiling data from four studies analylzing 305 breast tumors. The authors also analyze GATA-3 expression in 139 tumors using tissue microarrays. Low expression was strongly correlated with poor clinical outcome, positive lymph nodes, large tumor size, ER-/PR- status, and Her2-Neu overexpression. Cox multivariate analysis revealed the independent prognostic significance of GATA-3 in breast cancer.
• 45. Jenssen TK, Kuo WP, Stokke T, Hovig E. Associations between gene expressions in breast cancer and patient survival. Hum Genet. 2002;111:411–420. [PubMed]Log-rank analysis of microarray data from the Sorlie, 2001 data set [43] revealed that GATA-3 expression was the 2nd best predictor of breast cancer survival among 8024 genes, with its low expression indicating a poor prognosis.
46. Dolled-Filhart M, Ryden L, Cregger M, Jirstrom K, Harigopal M, Camp RL, Rimm DL. Classification of breast cancer using genetic algorithms and tissue microarrays. Clin Cancer Res. 2006;12:6459–6468. [PubMed]
47. Usary J, Llaca V, Karaca G, Presswala S, Karaca M, He X, Langerod A, Karesen R, Oh DS, Dressler LG, et al. Mutation of GATA3 in human breast tumors. Oncogene. 2004;23:7669–7678. [PubMed]
•• 48. Kouros-Mehr H, Bechis SK, Slorach EM, Littlepage LE, Egeblad M, Ewald AJ, Pai S, Ho I, Werb Z. GATA-3 links tumor differentiation and dissemination in a luminal breast cancer model. Cancer Cell. 2008;13:141–152. [PMC free article] [PubMed]A hyperplasia transplant model with MMTV-PyMT transgenic mice was used to study the role of GATA-3 during breast cancer progression. Loss of GATA-3 marked the early stages of malignant progression, including the histologic transition from adenoma to early carcinoma and the onset of tumor dissemination. Retroviral expression of GATA-3 in late carcinomas induced cellular differentiation and repressed dissemination. The loss of GATA-3 during tumor progression involved the expansion of a GATA-3 negative tumor stem-cell like population persisting in early tumors.
49. Guy CT, Cardiff RD, Muller WJ. Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Mol Cell Biol. 1992;12:954–961. [PMC free article] [PubMed]
50. Lin EY, Jones JG, Li P, Zhu L, Whitney KD, Muller WJ, Pollard JW. Progression to malignancy in the polyoma middle T oncoprotein mouse breast cancer model provides a reliable model for human diseases. Am J Pathol. 2003;163:2113–2126. [PMC free article] [PubMed]
51. Cheng G, Weihua Z, Warner M, Gustafsson JA. Estrogen receptors ER alpha and ER beta in proliferation in the rodent mammary gland. Proc Natl Acad Sci U S A. 2004;101:3739–3746. [PMC free article] [PubMed]
52. Eeckhoute J, Keeton EK, Lupien M, Krum SA, Carroll JS, Brown M. Positive cross-regulatory loop ties GATA-3 to estrogen receptor alpha expression in breast cancer. Cancer Res. 2007;67:6477–6483. [PubMed]
53. Mallepell S, Krust A, Chambon P, Brisken C. Paracrine signaling through the epithelial estrogen receptor alpha is required for proliferation and morphogenesis in the mammary gland. Proc Natl Acad Sci U S A. 2006;103:2196–2201. [PMC free article] [PubMed]
54. El Wakil A, Francius C, Wolff A, Pleau-Varet J, Nardelli J. The GATA2 transcription factor negatively regulates the proliferation of neuronal progenitors. Development. 2006 [PubMed]
55. Green KA, Carroll JS. Oestrogen-receptor-mediated transcription and the influence of co-factors and chromatin state. Nat Rev Cancer. 2007;7:713–722. [PubMed]
56. Carroll JS, Liu XS, Brodsky AS, Li W, Meyer CA, Szary AJ, Eeckhoute J, Shao W, Hestermann EV, Geistlinger TR, et al. Chromosome-wide mapping of estrogen receptor binding reveals long-range regulation requiring the forkhead protein FoxA1. Cell. 2005;122:33–43. [PubMed]
57. Laganiere J, Deblois G, Lefebvre C, Bataille AR, Robert F, Giguere V. From the Cover: Location analysis of estrogen receptor alpha target promoters reveals that FOXA1 defines a domain of the estrogen response. Proc Natl Acad Sci U S A. 2005;102:11651–11656. [PMC free article] [PubMed]
PubReader format: click here to try


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


  • MedGen
    Related information in MedGen
  • PubMed
    PubMed citations for these articles

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...