Mutation of GATA3 in human breast tumors

Usary, Jerry; Llaca, Víctor; Karaca, Gamze; Presswala, Shafaq; Karaca, Mehmet; He, Xiaping; Langerød, Anita; Kåresen, Rolf; Oh, Daniel S.; Dressler, Lynn G.; Lønning, Per Eystein; Strausberg, Robert L.; Chanock, Stephen J.; Børresen-Dale, Anne Lise; Perou, Charles M.

doi:10.1038/sj.onc.1207966

Cited by 245 publications

(293 citation statements)

References 42 publications

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“…The prevalence of GATA3 mutations in the current DCIS cohort is significantly higher than that reported in invasive breast cancer (4-22%) 4,5,30,31 and in DCIS. Recently, Abba et al 14 reported a GATA3 mutation rate of 7% in 30 pure high grade DCIS cases while Kim et al 15 observed GATA3 mutation in one low grade DCIS out of a cohort of in six DCIS lesions of various nuclear grades (16.7%).…”

Section: Discussioncontrasting

confidence: 67%

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Breast ductal carcinoma in situ carry mutational driver events representative of invasive breast cancer

et al. 2017

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The spectrum of genomic alterations in ductal carcinoma in situ (DCIS) is relatively unexplored, but is likely to provide useful insights into its biology, its progression to invasive carcinoma and the risk of recurrence. DCIS (n = 20) with a range of phenotypes was assessed by massively parallel sequencing for mutations and copy number alterations and variants validated by Sanger sequencing. PIK3CA mutations were identified in 11/20 (55%), TP53 mutations in 6/20 (30%), and GATA3 mutations in 9/20 (45%). Screening an additional 91 cases for GATA3 mutations identified a final frequency of 27% (30/111), with a high proportion of missense variants (8/30). TP53 mutations were exclusive to high grade DCIS and more frequent in PR-negative tumors compared with PR-positive tumors (P = 0.037). TP53 mutant tumors also had a significantly higher fraction of the genome altered by copy number than wild-type tumors (P = 0.005), including a significant positive association with amplification or gain of ERBB2 (Po 0.05). The association between TP53 mutation and ERBB2 amplification was confirmed in a wider DCIS cohort using p53 immunohistochemistry as a surrogate marker for TP53 mutations (P = 0.03). RUNX1 mutations and MAP2K4 copy number loss were novel findings in DCIS. Frequent copy number alterations included gains on 1q, 8q, 17q, and 20q and losses on 8p, 11q, 16q, and 17p. Patterns of genomic alterations observed in DCIS were similar to those previously reported for invasive breast cancers, with all DCIS having at least one bona fide breast cancer driver event. However, an increase in GATA3 mutations and fewer copy number changes were noted in DCIS compared with invasive carcinomas. The role of such alterations as prognostic and predictive biomarkers in DCIS is an avenue for further investigation.

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Section: Discussioncontrasting

confidence: 67%

“…4,5,30,31 We therefore evaluated GATA3 mutation status in a further 91 pure DCIS cases using Sanger sequencing of exons 5 and 6 (as DNA was limited). Nonsynonymous or splice region mutations were identified in 21/91 cases (23%, Supplementary Table 1), for a final frequency of 30/111 cases (27%).…”

Section: Mutated Genes In Dcismentioning

confidence: 99%

Breast ductal carcinoma in situ carry mutational driver events representative of invasive breast cancer

et al. 2017

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“…Loss of GATA3 function is associated with increased tumorigenesis and was found to be enriched in non-BRCA1/BRCA2 familial breast cancers (Arnold et al, 2010). Somatic GATA3 mutations have also been detected in Luminal A and B subtypes suggesting that and it is thought that GATA3 may confer a generalized growth inhibitory phenotype across a number of different tumor types (Usary et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

BRCA1 and GATA3 corepress FOXC1 to inhibit the pathogenesis of basal-like breast cancers

et al. 2011

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In this study we describe a novel interaction between the breast/ovarian tumor suppressor gene BRCA1 and the transcription factor GATA3, an interaction, which is important for normal breast differentiation. We show that the BRCA1-GATA3 interaction is important for the repression of genes associated with triple-negative and basal-like breast cancer (BLBCs) including FOXC1, and that GATA3 interacts with a C-terminal region of BRCA1. We demonstrate that FOXC1 is an essential survival factor maintaining the proliferation of BLBCs cell lines. We define the mechanistic basis of this corepression and identify the GATA3-binding site within the FOXC1 distal promoter region. We show that BRCA1 and GATA3 interact on the FOXC1 promoter and that BRCA1 requires GATA3 for recruitment to this region. This interaction requires fully functional BRCA1 as a mutant BRCA1 protein is unable to localize to the FOXC1 promoter or repress FOXC1 expression. We demonstrate that this BRCA1-GATA3 repression complex is not a FOXC1-specific phenomenon as a number of other genes associated with BLBCs such as FOXC2, CXCL1 and p-cadherin were also repressed in a similar manner. Finally, we demonstrate the importance of our findings by showing that loss of GATA3 expression or aberrant FOXC1 expression contributes to the drug resistance and epithelial-to-mesenchymal transition-like phenotypes associated with aggressive BLBCs.

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“…Defining the molecular and cellular basis of this process is essential for understanding mammary development and associated defects, including breast cancer. The fact that breast cancer stem cells share some characteristics with mammary stem cells (Al-Hajj et al, 2003;Visvader and Lindeman, 2008) and that mutations in a number of the genes associated with mammary development have also been implicated in breast cancer (Usary et al, 2004;Bogorad et al, 2008) suggests that studies on mammary development may help define the early events that precede breast tumourigenesis.…”

Section: Introductionmentioning

confidence: 99%

Analysis of Brca1-deficient mouse mammary glands reveals reciprocal regulation of Brca1 and c-kit

et al. 2010

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Disruption of the breast cancer susceptibility gene Brca1 results in defective lobular-alveolar development in the mammary gland and a predisposition to breast tumourigenesis in humans and in mice. Recent evidence suggests that BRCA1 loss in humans is associated with an expansion of the luminal progenitor cell compartment in the normal breast and tumours with a luminal progenitorlike expression profile. To further investigate the role of BRCA1 in the mammary gland, we examined the consequences of Brca1 loss in mouse mammary epithelial cells in vitro and in vivo. Here, we show that Brca1 loss is associated with defective morphogenesis of SCp2 and HC11 mouse mammary epithelial cell lines and that in the MMTV-Cre Brca1 Co/Co mouse model of Brca1 loss, there is an accumulation of luminal progenitor (CD61 þ CD29 lo CD24 þ ) cells during pregnancy. By day 1 of lactation, there are marked differences in the expression of 1379 genes, with most significantly altered pathways and networks, including lactation, the immune response and cancer. One of the most differentially expressed genes was the luminal progenitor marker, c-kit. Immunohistochemical analysis revealed that the increase in c-kit levels is associated with an increase in c-kit positivity. Interestingly, an inverse association between Brca1 and c-kit expression was also observed during mammary epithelial differentiation, and small interfering RNA-mediated knockdown of Brca1 resulted in a significant increase in c-kit mRNA levels. We found no evidence that c-kit plays a direct role in regulating differentiation of HC11 cells, suggesting that Brca1-mediated induction of c-kit probably contributes to Brca1-associated tumourigenesis via another cellular process, and that c-kit is likely to be a marker rather than a mediator of defective lobular-alveolar development resulting from Brca1 loss.

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Mutation of GATA3 in human breast tumors

Cited by 245 publications

References 42 publications

Breast ductal carcinoma in situ carry mutational driver events representative of invasive breast cancer

Breast ductal carcinoma in situ carry mutational driver events representative of invasive breast cancer

BRCA1 and GATA3 corepress FOXC1 to inhibit the pathogenesis of basal-like breast cancers

Analysis of Brca1-deficient mouse mammary glands reveals reciprocal regulation of Brca1 and c-kit

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