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GATA-3 links tumor differentiation and dissemination in a luminal breast cancer model.

ABSTRACT: How breast cancers are able to disseminate and metastasize is poorly understood. Using a hyperplasia transplant system, we show that tumor dissemination and metastasis occur in discrete steps during tumor progression. Bioinformatic analysis revealed that loss of the transcription factor GATA-3 marked progression from adenoma to early carcinoma and onset of tumor dissemination. Restoration of GATA-3 in late carcinomas induced tumor differentiation and suppressed tumor dissemination. Targeted deletion of GATA-3 in early tumors led to apoptosis of differentiated cells, indicating that its loss is not sufficient for malignant conversion. Rather, malignant progression occurred with an expanding GATA-3-negative tumor cell population. These data indicate that GATA-3 regulates tumor differentiation and suppresses tumor dissemination in breast cancer.

SUBMITTER: Kouros-Mehr H

PROVIDER: S-EPMC2262951 | biostudies-literature | 2008 Feb

REPOSITORIES: biostudies-literature

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GATA-3 links tumor differentiation and dissemination in a luminal breast cancer model.

Kouros-Mehr Hosein H Bechis Seth K SK Slorach Euan M EM Littlepage Laurie E LE Egeblad Mikala M Ewald Andrew J AJ Pai Sung-Yun SY Ho I-Cheng IC Werb Zena Z

Cancer cell 20080201 2

How breast cancers are able to disseminate and metastasize is poorly understood. Using a hyperplasia transplant system, we show that tumor dissemination and metastasis occur in discrete steps during tumor progression. Bioinformatic analysis revealed that loss of the transcription factor GATA-3 marked progression from adenoma to early carcinoma and onset of tumor dissemination. Restoration of GATA-3 in late carcinomas induced tumor differentiation and suppressed tumor dissemination. Targeted dele ...[more]

PMID: 18242514

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Project description:IntroductionKi-67 labeling index assessed by immunohistochemical assays has been shown useful in assessing the risk of recurrence for estrogen receptor (ER)-positive HER2-negative breast cancers (BC) and distinguishing Luminal A-like from Luminal B-like tumors. We aimed to assess the performance of the Ventana CONFIRM anti-Ki-67 (30-9) Rabbit Monoclonal Primary Antibody.MethodsWe constructed a case-cohort design based on a random sample (n?=?679) of all patients operated on for a first primary, non-metastatic, ER-positive, HER2-negative BC at the European Institute of Oncology (IEO) Milan, Italy during 1998-2002 and all additional patients (n?=?303) operated during the same period, who developed an event (metastasis in distant organs or death due to BC as primary event) and were not included in the previous subset. Multivariable Cox proportional hazards regression with inverse subcohort sampling probability weighting was used to evaluate the risk of event according to Ki-67 (30-9) and derived intrinsic molecular subtype, using previously defined cutoff values, i.e., respectively 14% and 20%.ResultsKi-67 was?<?14% in 318 patients (32.4%), comprised between 14 and 19% in 245 patients (24.9%) and???20 in 419 patients (42.7%). At multivariable analysis, the risk of developing distant disease was 1.88 (95% CI 1.20-2.93; P?=?0.006) for those with Ki-67 comprised between 14 and 19%, and 3.06 (95% CI 1.93-4.84; P?<?0.0001) for those with Ki-67???20% compared to those with Ki-67?<?14%. Patients with Luminal B-like BC had an approximate twofold risk of developing distant disease (HR?=?1.91; 95% CI 1.35-2.71; P?=?0.0003) than patients with Luminal A-like BC defined using Ki-67 (30-9).ConclusionsKi-67 evaluation using the 30-9 rabbit monoclonal primary antibody was able to stratify patients with ER-positive HER2-negative BC into prognostically distinct groups. Ki-67 assessment, with strict adherence to the international recommendations, should be included among the clinically useful biological parameters for the best treatment of patients with BC.

Project description:Background: The tumor microenvironment (TME) has been reported to have significant value in the diagnosis and prognosis of cancers. This study aimed to identify key biomarkers in the TME of luminal breast cancer (BC). Methods: We obtained immune scores (ISs) and stromal scores (SSs) for The Cancer Genome Atlas (TCGA) luminal BC cohort from the online ESTIMATE (Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data) portal. The relationships between ISs and SSs and the overall survival of luminal BC patients were assessed by the Kaplan-Meier method. The differentially expressed messenger RNAs (DEmRNAs) related to the ISs and SSs were subjected to functional enrichment analysis. Additionally, a competing endogenous RNA (ceRNA) network was constructed with differentially expressed microRNAs (DEmiRNAs) and long noncoding RNAs (DElncRNAs). Furthermore, a protein-protein interaction (PPI) network was established to analyze the DEmRNAs in the ceRNA network. Then, survival analysis of biomarkers involved in the ceRNA network was carried out to explore their prognostic value. Finally, these biomarkers were validated using the luminal BC dataset from the Gene Expression Omnibus (GEO) database. Results: The results showed that ISs were significantly associated with longer survival times of luminal BC patients. Functional enrichment analysis showed that the DEmRNAs were mainly associated with immune response, antigen binding, and the extracellular region. In the PPI network, the top 10 DEmRNAs were identified as hub genes that affected the TME of luminal BC. Finally, two DEmiRNAs, two DElncRNAs, and 17 DEmRNAs of the ceRNA network associated with the TME were shown to have prognostic value. Subsequently, the expression of 15 prognostic biomarkers was validated in one additional dataset (GSE81002). In particular, one lncRNA (GVINP1) and five mRNAs (CCDC69, DOCK2, IKZF1, JCHAIN, and NCKAP1L) were novel biomarkers. Conclusions: Our studies demonstrated that ISs were associated with the survival of luminal BC patients, and a set of novel biomarkers that might play a prognostic role in the TME of luminal BC was identified.

Dataset Information

GATA-3 links tumor differentiation and dissemination in a luminal breast cancer model.

Publications

GATA-3 links tumor differentiation and dissemination in a luminal breast cancer model.

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