Mutant GATA3 Actively Promotes the Growth of Normal and Malignant Mammary Cells

Emmanuel, Natasha; Lofgren, Kristopher A.; Peterson, Esther A.; Meier, David R.; Jung, Eric H.; Kenny, Paraic A.

doi:10.21873/anticanres.12745

Cited by 31 publications

(30 citation statements)

References 29 publications

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“…Notably, this was the case for the missense mutation of the tumor suppressor ARID1A in MBC1 and MBC2 PDXs or for GATA3 insertion in MBC3 (Table S2). The appearance of new mutations in PDX1 might be the consequence of some degree of clonal selection during in vivo growth, since mutations of ARID1A are associated with increased cellular proliferation and have been reported in a variety of human cancers [25]. Finally, Pearson correlations were extremely high among PDXs at different passages (Supplementary Figure S1E), supporting high genome stability upon serial transplantation in mice.…”

Section: Resultsmentioning

confidence: 63%

Development of Personalized Therapeutic Strategies by Targeting Actionable Vulnerabilities in Metastatic and Chemotherapy-Resistant Breast Cancer PDXs

Punzi

Meliksetian

Riva

et al. 2019

Cells

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Human breast cancer is characterized by a high degree of inter-patients heterogeneity in terms of histology, genomic alterations, gene expression patterns, and metastatic behavior, which deeply influences individual prognosis and treatment response. The main cause of mortality in breast cancer is the therapy-resistant metastatic disease, which sets the priority for novel treatment strategies for these patients. In the present study, we demonstrate that Patient Derived Xenografts (PDXs) that were obtained from metastatic and therapy-resistant breast cancer samples recapitulate the wide spectrum of the disease in terms of histologic subtypes and mutational profiles, as evaluated by whole exome sequencing. We have integrated genomic and transcriptomic data to identify oncogenic and actionable pathways in each PDX. By taking advantage of primary short-term in vitro cultures from PDX tumors, we showed their resistance to standard chemotherapy (Paclitaxel), as seen in the patients. Moreover, we selected targeting drugs and analyzed PDX sensitivity to single agents or to combination of targeted and standard therapy on the basis of PDX-specific genomic or transcriptomic alterations. Our data demonstrate that PDXs represent a suitable model to test new targeting drugs or drug combinations and to prioritize personalized therapeutic regimens for pre-clinal and clinical tests.

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Section: Resultsmentioning

confidence: 63%

Development of Personalized Therapeutic Strategies by Targeting Actionable Vulnerabilities in Metastatic and Chemotherapy-Resistant Breast Cancer PDXs

Punzi

Meliksetian

Riva

et al. 2019

Cells

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“…Regarding to the higher level of expression in tumor samples ( GATA3 mutant and non-mutant) than normal ones, a meta-analysis study confirmed the relation between GATA3 overexpression and favorable phenotypes including ER-positive status 14 . On the other hand, a cell line study indicated the active GATA3 transcription factors cause proliferative phenotypes and promote the growth of ER-positive breast cancer cell lines 37 . In addition to the impact of the mutation on expression level, somatic mutations may affect the binding site and influence the rate of downstream genes expression and result in a changed transcriptional network 36 , 38 .…”

Section: Discussionmentioning

confidence: 99%

GATA3 somatic mutations are associated with clinicopathological features and expression profile in TCGA breast cancer patients

Afzaljavan

Sadr

Savas

et al. 2021

Sci Rep

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The effect of somatic mutations and the gene expression profiles on the prognosis is well documented in cancer research. This study was conducted to evaluate the association of GATA3 somatic mutations with tumor features, survival, and expression profiles in breast cancer. Clinicopathological information was compared between TCGA-BRCA patients with GATA3-mutant and non-mutant tumors in all patients as well as in ER-positive subgroup. Cox-regression method was used to evaluate the association of the GATA3 mutation status with overall survival time. Differential gene expression, functional annotation, and protein–protein interaction analyses were performed using edgeR, Metascape, DAVID, STRING and CytoNCA. GATA3-mutant and non-mutant samples had significantly different clinicopathological features (p < 0.05). While GATA3 mutation status was not associated with the overall survival in the entire cohort (padj = 0.52), the GATA3-wild type ER-positive cases had a better prognosis than mutant ones (padj = 0.04). GATA3 expression was higher in tumors than normal tissues. Several pathways were different between mutant and non-mutant groups (p < 0.05). Interleukin-6 was found as the highest scored gene in both comparisons (normal vs. mutant and normal vs. non-mutant groups) in the entire patient and in the ER-positive subgroup, suggesting the association of IL6 with breast tumorigenesis. These findings suggest that GATA3 mutations can be associated with several tumor characteristics and influence the pattern of gene expression. However, GATA3 mutation status seems to be a prognostic factor for the disease only in ER-positive patients.

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“…We also experimentally demonstrated that one of these mutations (R330fs: a heterozygous frame-shift mutation at arginine 330) induces alterations of GATA3 chromatin binding activities leading to more aggressive tumor phenotypes in vitro and in vivo (21). Other groups also observed similar aggressive cell characteristics in breast cancer cells that express another ZnFn2 mutation (D336fs: a heterozygous frame-shift mutation at aspartic acid 336) (22)(23)(24). The phenotypic alterations are partially explained by the action of the mutant protein (9,21,25).…”

Section: Introductionmentioning

confidence: 65%

GATA3 mutation disrupts a functional network governed by estrogen receptor, FOXA1 and GATA3

Takaku

Grimm

Kumar

et al. 2019

Preprint

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Estrogen receptors (ER) are part of the nuclear receptor superfamily of transcription factors and are activated by the steroid hormone 17b-estradiol. ER forms a regulatory network in conjunction with other transcription factors, such as FOXA1 and GATA3. GATA3 has been identified as one of the most frequently mutated genes in breast cancer and is capable of specifying chromatin localization of FOXA1 and ER. How GATA3 mutations impact this transcriptional network is unknown. Here we investigate the function of one of the recurrent patient-derived GATA3 mutations (R330fs) on this regulatory network. Genomic analysis indicates that the R330fs mutant can disrupt the cooperative action of ER, FOXA1, and GATA3, and induce a change in chromatin localization of these factors. Relocalization of ER and FOXA1 is associated with altered chromatin architecture, which leads to differential gene expression in GATA3 mutant cells. These results suggest an active role for GATA3 mutants in ER positive breast tumors. Predicted status Z-score Activated 2.14 Activated 3.46 Activated 2.62 Activated 2.69 Activated 2.25 FOXA1 decreased ER increased FOXA1 increased

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Mutant GATA3 Actively Promotes the Growth of Normal and Malignant Mammary Cells

Cited by 31 publications

References 29 publications

Development of Personalized Therapeutic Strategies by Targeting Actionable Vulnerabilities in Metastatic and Chemotherapy-Resistant Breast Cancer PDXs

Development of Personalized Therapeutic Strategies by Targeting Actionable Vulnerabilities in Metastatic and Chemotherapy-Resistant Breast Cancer PDXs

GATA3 somatic mutations are associated with clinicopathological features and expression profile in TCGA breast cancer patients

GATA3 mutation disrupts a functional network governed by estrogen receptor, FOXA1 and GATA3

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