GATA3 and the regulation of the mammary luminal cell fate

Breast Cancer Research, 2014

Introduction: GATA binding protein 3 (GATA3) is a regulator of mammary luminal cell differentiation, and an estrogen receptor (ER) associated marker in breast cancer. Tumor suppressor functions of GATA3 have been demonstrated primarily in basal-like breast cancers. Here, we focused on its function in luminal breast cancer, where GATA3 is frequently mutated, and its levels are significantly elevated. Methods: GATA3 target genes were identified in normal-and luminal cancer-mammary cells by ChIP-seq, followed by examination of the effects of GATA3 expressions and mutations on tumorigenesis-associated genes and processes. Additionally, mutations and expression data of luminal breast cancer patients from The Cancer Genome Atlas were analyzed to characterize genetic signatures associated with GATA3 mutations. Results: We show that some GATA3 effects shift from tumor suppressing to tumor promoting during tumorigenesis, with deregulation of three genes, BCL2, DACH1, THSD4, representing major GATA3-controlled processes in cancer progression. In addition, we identify an altered activity of mutant GATA3, and distinct associated genetic signatures. These signatures depend on the functional domain mutated; and, for a specific subgroup, are shared with basal-like breast cancer patients, who are a clinical group with regard to considerations of mode of treatment. Conclusions: The GATA3 dependent mechanisms may call for special considerations for proper prognosis and treatment of patients.

Molecular and Cellular Biology, 2011

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.

Journal of Toxicologic Pathology

The GATA family members are zinc finger transcription factors involved in cell differentiation and proliferation. In particular, GATA-3 is necessary for mammary gland maturation and is a useful marker in the characterization of mammary carcinoma in humans. The expression of GATA-3 protein in normal mammary glands, fibroadenomas and carcinomas was immunohistochemically compared in female rats and humans. In normal mammary glands of rats and humans, scattered luminal cells in the acini and whole ductal epithelial cells were positive for GATA-3 in the nuclei. No positive cells were detected in rat or human fibroadenomas. In rat and human mammary carcinomas, the nuclei of proliferating luminal-derived cancer cells expressed GATA-3. Therefore, GATA-3 protein is a candidate marker for mammary carcinoma in rats as well as humans.

Breast Cancer Research, 2014

Introduction: The transcription factor GATA3 is involved in mammary gland development and is crucial for the maintenance of the differentiated status of luminal epithelial cells. The role of GATA3 in breast cancer as a tumor suppressor has been established, although insights into the mechanism of GATA3 expression loss are still required. Methods: Chromatin immunoprecipitation assays were conducted to study progestin modulation of recruitment of transcription factors to GATA3 promoter. We performed western blot and reverse RT-qPCR experiments to explore progestin regulation of GATA3 protein and mRNA expression respectively. Confocal microscopy and in vitro phosphorylation studies were conducted to examine progestin capacity to induce GATA3 serine phosphorylation in its 308 residue. GATA3 participation in progestin-induced breast cancer growth was addressed in in vitro proliferation and in vivo tumor growth experiments.

Annals of Pathology and Laboratory Medicine, 2021

Background: GATA3 plays an essential role in the normal development and function of the mammary gland where it promotes the luminal transcriptional program. Its loss is implicated in the pathogenesis of breast cancer. We proposed to study the expression of GATA3 in carcinoma breast by immunohistochemistry and determine its correlation with prognostic parameters. Methods: The expression pattern of GATA3 was evaluated by immunohistochemistry in 30 cases of invasive breast carcinoma. GATA3 scoring was done and a score of ≥ 1+ was considered positive. Patient characteristics, including age, tumour laterality, tumour size, lymph node status, tumour grade, histological type, molecular subtypes were collected. The relationships between protein expression and clinicopathological variables were analysed. Statistical significance was determined by Pearson’s chi-square test and Mann Whitney U test (for age). Result: 46.7% of cases (14/30) scored positive for GATA3 expression in tumour cells in...

Human Pathology, 2010

The GATA family members are zinc finger transcription factors involved in cell differentiation and proliferation. GATA3 in particular is necessary for mammary gland maturation, and its loss has been implicated in breast cancer development. Our goal was to validate the ability of GATA3 expression to predict survival in breast cancer patients. Protein expression of GATA3 was analyzed on a high density tissue microarray consisting of 242 cases of breast cancer. We associated GATA3 expression with patient outcomes and clinicopathological variables. Expression of GATA3 was significantly increased in breast cancer, in situ lesions, and hyperplastic tissue compared to normal breast tissue. GATA3 expression decreased with increasing tumor grade. Low GATA3 expression was a significant predictor of disease-related death in all patients, as well as in subgroups of estrogen receptor positive or low grade patients. Additionally, low GATA3 expression correlated with increased tumor size and estrogen and progesterone receptor negativity. GATA3 is an important predictor of disease outcome in breast cancer patients. This finding has been validated in a diverse set of populations. Thus, GATA3 expression has utility as a prognostic indicator in breast cancer.

Cancer Cell, 2009

Mammary epithelia are composed of luminal and myoepithelial/basal cells whose neoplastic transformations lead to distinct types of breast cancers with diverse clinical features. We report that mice deficient for the CDK4/6 inhibitor p18 Ink4c spontaneously develop ER-positive luminal tumors at a high penetrance. Ink4c deletion stimulates luminal progenitor cell proliferation at pubertal age and maintains an expanded luminal progenitor cell population throughout life. We demonstrate that GATA3 binds to and represses INK4C transcription. In human breast cancers, low INK4C and high GATA3 expressions are simultaneously observed in luminal A type tumors and predict a favorable patient outcome. Hence, p18 INK4C is a downstream target of GATA3, constrains luminal progenitor cell expansion and suppresses luminal tumorigenesis in the mammary gland. SIGNIFICANCE-Breast cancer is heterogenous with tumors pathologically distinct and diverse in their responsiveness to treatment. We show that the CDK inhibitor p18 INK4c gene is repressed by GATA3, a transcription factor specifying mammary luminal cell fate, and that low INK4C and high GATA3 expressions are associated with human luminal A type tumors and with better patient survival. p18 Ink4c null mice have an expanded luminal progenitors at a young age and throughout life and develop ER + luminal tumors at high penetrance. These results identify the escape of luminal progenitors from quiescence as a rate-limiting step for initiation of mammary luminal tumors. The Ink4c-null mouse represents a unique model for study and for developing therapeutic strategies to treat luminal tumors.

2000

The transcription factor GATA-3 is required for normal mammary gland development, and its expression is highly correlated with estrogen receptor A (ERA)in human breast tumors. However, the functional role of GATA-3 in ERA- positive breast cancers is yet to be established. Here, we show that GATA-3 is required for estradiol stimulation of cell cycle progression in breast cancer cells. The

Cancer Research, 2007

The transcription factor GATA-3 is required for normal mammary gland development, and its expression is highly correlated with estrogen receptor A (ERA) in human breast tumors. However, the functional role of GATA-3 in ERApositive breast cancers is yet to be established. Here, we show that GATA-3 is required for estradiol stimulation of cell cycle progression in breast cancer cells. The role of GATA-3 in estradiol signaling requires the direct positive regulation of the expression of the ERa gene itself by GATA-3. GATA-3 binds to two cis-regulatory elements located within the ERa gene, and this is required for RNA polymerase II recruitment to ERa promoters. Reciprocally, ERA directly stimulates the transcription of the GATA-3 gene, indicating that these two factors are involved in a positive cross-regulatory loop. Moreover, GATA-3 and ERA regulate their own expression in breast cancer cells. Hence, this transcriptional coregulatory mechanism accounts for the robust coexpression of GATA-3 and ERA in human breast cancers. In addition, these results highlight the crucial role of GATA-3 for the response of ERA-positive breast cancers to estradiol. Moreover, they identify GATA-3 as a critical component of the master cell-type-specific transcriptional network including ERA and FoxA1 that dictates the phenotype of hormone-dependent breast cancer. [Cancer Res 2007;67(13):6477-83]

Cancer research, 2007

The transcription factor GATA-3 is required for normal mammary gland development, and its expression is highly correlated with estrogen receptor A (ERA) in human breast tumors. However, the functional role of GATA-3 in ERApositive breast cancers is yet to be established. Here, we show that GATA-3 is required for estradiol stimulation of cell cycle progression in breast cancer cells. The role of GATA-3 in estradiol signaling requires the direct positive regulation of the expression of the ERa gene itself by GATA-3. GATA-3 binds to two cis-regulatory elements located within the ERa gene, and this is required for RNA polymerase II recruitment to ERa promoters. Reciprocally, ERA directly stimulates the transcription of the GATA-3 gene, indicating that these two factors are involved in a positive cross-regulatory loop. Moreover, GATA-3 and ERA regulate their own expression in breast cancer cells. Hence, this transcriptional coregulatory mechanism accounts for the robust coexpression of GATA-3 and ERA in human breast cancers. In addition, these results highlight the crucial role of GATA-3 for the response of ERA-positive breast cancers to estradiol. Moreover, they identify GATA-3 as a critical component of the master cell-type-specific transcriptional network including ERA and FoxA1 that dictates the phenotype of hormone-dependent breast cancer. [Cancer Res 2007;67(13):6477-83]

mjpath.org.my

The GATA3 gene is a potential tumour marker and putative tumour suppressor gene in breast cancer. Its expression is associated with better prognosis and disease free survival in breast cancer patients. We aimed to evaluate GATA3 transcriptome expression and mutation in breast carcinomas and correlate its expression with oestrogen receptor (ER), progesterone receptor (PR), lymph node (LN) status, tumour grade and c-erbB-2 expression. Twenty-two breast infi ltrating ductal carcinomas and paired normal tissues were used in Branch DNA assay to detect GATA3 mRNA expression. Normalized data for GATA3 mRNA expression were grouped according to the ER, PR and LN status, tumour grade and c-erbB-2 expression of the tumours. Statistical signifi cance was tested using t-test and ANOVA at 95% confi dence interval level. Mutational analysis of GATA3 was performed by direct sequencing of the coding regions of GATA3 mRNA. Our fi ndings showed that GATA3 gene were over-expressed and under-expressed by >2 fold change in 12 and 4 tested samples, respectively. Eighty per cent of ER positive breast carcinomas were GATA3 positive. There was a statistically signifi cant correlation between GATA3 expression and ER at 95% confi dence interval level between the study groups. On the contrary, GATA3 expression was not statistically signifi cant with PR, LN, tumour grade and c-erbB-2 expression in our study. In addition, we observed that there was no mutation in mRNA coding region in 16 breast carcinomas that showed GATA3 differential gene expression. Our preliminary results suggested that GATA3 is linked to the ER. This scenario suggests that GATA3 may play a crucial role in oestrogen receptor positive breast cancer patients. Whether GATA3 expression is involved in regulating tumour cell growth in oestrogen responsive breast cancer is a key question that remains to be answered.

Oncogene, 2004

GATA3 is an essential transcription factor that was first identified as a regulator of immune cell function. In recent microarray analyses of human breast tumors, both normal breast luminal epithelium and estrogen receptor (ESR1)positive tumors showed high expression of GATA3. We sequenced genomic DNA from 111 breast tumors and three breast-tumor-derived cell lines and identified somatic mutations of GATA3 in five tumors and the MCF-7 cell line. These mutations cluster in the vicinity of the highly conserved second zinc-finger that is required for DNA binding. In addition to these five, we identified using cDNA sequencing a unique mis-splicing variant that caused a frameshift mutation. One of the somatic mutations we identified was identical to a germline GATA3 mutation reported in two kindreds with HDR syndrome/OMIM #146255, which is an autosomal dominant syndrome caused by the haplo-insufficiency of GATA3. The ectopic expression of GATA3 in human 293T cells caused the induction of 73 genes including six cytokeratins, and inhibited cell line doubling times. These data suggest that GATA3 is involved in growth control and the maintenance of the differentiated state in epithelial cells, and that GATA3 variants may contribute to tumorigenesis in ESR1-positive breast tumors.

Journal of Biological Chemistry, 2010

GATA3, a transcription factor that regulates T lymphocyte differentiation and maturation, is exclusively expressed in early stage well differentiated breast cancers but not in advanced invasive cancers. However, little is understood regarding its activity and the mechanisms underlying this differential expression in cancers. Here, we employed GATA3-positive, non-invasive (MCF-7) and GATA3-negative, invasive (MDA-MB-231) breast cancer cells to define its role in the transformation between these two distinct phenotypes. Ectopic expression of GATA3 in MDA-MB-231 cells led to a cuboidal-like epithelial phenotype and reduced cell invasive activity. These cells also increased E-cadherin expression but decreased levels of vimentin, N-cadherin, and MMP-9. Further, MDA-MB-231 cells expressing GATA3 grew smaller primary tumors without metastasis compared with larger metastatic tumors derived from control MDA-MB-231 cells in xenografted mice. GATA3 was found to induce E-cadherin expression through binding GATA-like motifs located in the E-cadherin promoter. Blockade of GATA3 using small interfering RNA gene knockdown in MCF-7 cells triggered fibroblastic transformation and cell invasion, resulting in distant metastasis. Studies of human breast cancer showed that GATA3 expression correlated with elevated E-cadherin levels, ER expression, and long disease-free survival. These data suggest that GATA3 drives invasive breast cancer cells to undergo the reversal of epithelial-mesenchymal transition, leading to the suppression of cancer metastasis. GATA3 (GATA-binding protein 3) is a family member of zinc finger transcription factors (GATA1-GATA6) that bind with high affinity to the consensus DNA sites (T/A-GATA-A/G) (1, 2). GATA1, GATA2, and GATA3 are primarily expressed by hematopoietic cells, whereas GATA4, GATA5, and GATA6 are detectable in the cardiovascular system and endodermus-derived tissues, such as lung, liver, intestine, and pancreas (3). Functional studies of GATA3 in the lineage specification of hematopoietic cells have revealed that GATA3

Cancer Research, 2005

GATA binding protein 3 (GATA3) is a transcriptional activator highly expressed by the luminal epithelial cells in the breast.

Oncogene

As the catalog of oncogenic driver mutations is expanding, it becomes clear that alterations in a given gene might have different functions and should not be lumped into one class. The transcription factor GATA3 is a paradigm of this. We investigated the functions of the most common GATA3 mutation (X308_Splice) and five additional mutations, which converge into a neoprotein that we called “neoGATA3,” associated with excellent prognosis in patients. Analysis of available molecular data from >3000 breast cancer patients revealed a dysregulation of the ER-dependent transcriptional response in tumors carrying neoGATA3-generating mutations. Mechanistic studies in vitro showed that neoGATA3 interferes with the transcriptional programs controlled by estrogen and progesterone receptors, without fully abrogating them. ChIP-Seq analysis indicated that ER binding is reduced in neoGATA3-expressing cells, especially at distal regions, suggesting that neoGATA3 interferes with the fine tuning o...