Transcriptional changes associated with overexpression of TBX3 isoforms (TBX3iso1 and TBX3iso2) in the DCIS-like 21NT cell line
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ABSTRACT:
PROVIDER: PRJNA521156 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8539651.fastq.gz | Fastqsanger.gz | |||
| SRR8539652.fastq.gz | Fastqsanger.gz | |||
| SRR8539653.fastq.gz | Fastqsanger.gz | |||
| SRR8539654.fastq.gz | Fastqsanger.gz | |||
| SRR8539655.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: The acquisition of cellular invasiveness of breast epithelial cells and subsequent transition from ductal carcinoma in situ (DCIS) to invasive breast cancer is a critical step in breast cancer progression. Very little is known about the molecular dynamics governing this transition. We have previously shown that overexpression of the transcriptional regulator TBX3 in DCIS-like 21NT cells results in increased survival, growth, and invasiveness. In this study we explore the role of TBX3 in breast cancer progression pathways, focusing specifically on its involvement in the induction of EMT and the transition from DCIS to invasive mammary carcinoma. Methods: Total mRNA was isolated from 21NT transfected cell lines. Sequencing was conducted using an Illumina HiSeq 2500 sequencer, comparing the resultant transcriptional profiles with overexpression of either TBX3 isoform (TBX3iso1 or TBX3iso2) as fold changes relative to the empty vector control. RNA-Seq data was integrated with ChIP-array data downstream to assess direct targets of TBX3 isoforms and relate it to the process of EMT. TBX3, SLUG and TWIST1 expression were assessed by immunohistochemistry in two independent early-stage (Stage 0 and Stage 1) breast cancer cohorts. Results: An EMT-related transcriptional profile was observed with overexpression of TBX3iso1 and TBX3iso2. Using genome-wide bioinformatic approaches in conjunction with more conventional in vitro studies, we have identified SLUG and TWIST1 as downstream targets of TBX3 and have assessed their expression by immunohistochemistry in two different patient cohorts. Our findings suggest that TBX3 facilitates the process of early invasion in DCIS lesions by promoting the induction of EMT and tumor progression through the low-grade pathway. Finally, we propose a progression model in which SLUG is an important and necessary effector downstream of TBX3, leading to increased motility, invasiveness, and induction of key invasiveness-associated genes. Conclusions: This is the only existing study which has conducted assessment of transcriptional changes associated with TBX3 isoforms (TBX3iso1 and TBX3iso2). Our published study has identified the transcriptional regulator TBX3 as an enabler of EMT in non-high grade, pre-invasive lesions of the breast, inducing SLUG and promoting the transition from in situ (DCIS) to invasive breast cancer.
2019-02-07 | GSE126154 | GEO
Project description:Purpose: The acquisition of cellular invasiveness of breast epithelial cells and subsequent transition from ductal carcinoma in situ (DCIS) to invasive breast cancer is a critical step in breast cancer progression. Very little is known about the molecular dynamics governing this transition. We have previously shown that overexpression of the transcriptional regulator TBX3 in DCIS-like 21NT cells results in increased survival, growth, and invasiveness. In this study we explore the role of TBX3 in breast cancer progression pathways, focusing specifically on its involvement in the induction of EMT and the transition from DCIS to invasive mammary carcinoma. Methods: Total mRNA was isolated from 21NT transfected cell lines. Sequencing was conducted using an Illumina HiSeq 2500 sequencer, comparing the resultant transcriptional profiles with overexpression of either TBX3 isoform (TBX3iso1 or TBX3iso2) as fold changes relative to the empty vector control. RNA-Seq data was integrated with ChIP-array data downstream to assess direct targets of TBX3 isoforms and relate it to the process of EMT. TBX3, SLUG and TWIST1 expression were assessed by immunohistochemistry in two independent early-stage (Stage 0 and Stage 1) breast cancer cohorts. Results: An EMT-related transcriptional profile was observed with overexpression of TBX3iso1 and TBX3iso2. Using genome-wide bioinformatic approaches in conjunction with more conventional in vitro studies, we have identified SLUG and TWIST1 as downstream targets of TBX3 and have assessed their expression by immunohistochemistry in two different patient cohorts. Our findings suggest that TBX3 facilitates the process of early invasion in DCIS lesions by promoting the induction of EMT and tumor progression through the low-grade pathway. Finally, we propose a progression model in which SLUG is an important and necessary effector downstream of TBX3, leading to increased motility, invasiveness, and induction of key invasiveness-associated genes. Conclusions: This is the only existing study which has conducted assessment of transcriptional changes associated with TBX3 isoforms (TBX3iso1 and TBX3iso2). Our published study has identified the transcriptional regulator TBX3 as an enabler of EMT in non-high grade, pre-invasive lesions of the breast, inducing SLUG and promoting the transition from in situ (DCIS) to invasive breast cancer.
2019-02-07 | GSE126153 | GEO
Project description:Transcriptional changes associated with overexpression of TBX3 isoforms (TBX3iso1 and TBX3iso2) in the DCIS-like 21NT cell line (ChIP)
| PRJNA521162 | ENA
Project description:Transcriptional changes associated with overexpression of TBX3 isoforms (TBX3iso1 and TBX3iso2) in the DCIS-like 21NT cell line (RNA-Seq)
| PRJNA521161 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2019-02-07 | GSE126156 | GEO
Project description:The Wnt/β-catenin signaling pathway plays crucial roles in nearly all parts of embryonic development and adult stem cell homeostasis. Its aberrant activation has been linked to many diseases such as developmental irregularities and various severe forms of cancer, with colorectal cancer (CRC) as a prime example. While much work has been dedicated to uncovering effective therapeutics to block oncogenic Wnt signaling, such interventions have not proven trivial because of the broad activity of Wnt throughout the adult body and the difficulty in finding suitable molecular targets. We have previously identified the developmental transcription factor TBX3 as a participant of the Wnt-mediated transcriptional regulation. Here, we performed Cap-Analysis Gene Expression sequencing (CAGE-seq) to assess the genome-wide transcriptional consequences upon TBX3 overexpression in the human colorectal cancer cell line HCT116.
2024-01-01 | E-MTAB-13647 | biostudies-arrayexpress
Project description:CAGE-seq of human colon cancer cell line (HCT116) upon TBX3 overexpression
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Project description:DCIS is a non-invasive precursor lesion to invasive breast carcinoma. We still have no understanding on why only some DCIS lesions evolve to invasive cancer while others appear not to do so during the life span of the patient. Here, we performed full exome (tumor vs. matching normal), transcriptome and methylome analysis of 30 pure high-grade DCIS (HG-DCIS) and 10 normal breast epithelial samples. Sixty two percent of HG-DCIS cases displayed mutations affecting cancer driver genes or potential drivers. Mutations were observed affecting PIK3CA (21% of cases), TP53 (17%), GATA3 (7%), MLL3 (7%) and single cases of mutations affecting CDH1, MAP2K4, TBX3, NF1, ATM and ARID1A. Significantly, 83% of lesions displayed numerous large chromosomal copy number alterations, suggesting they might precede selection of cancer driver mutations. Integrated pathway-based modeling analysis of RNA-seq data allowed us to identify two DCIS subgroups (DCIS-C1 and DCIS-C2) based on their tumor intrinsic subtypes, proliferative, immune scores and in the activity of specific signaling pathways. The more aggressive DCIS-C1 (highly proliferative, basal-like or ERBB2+) displayed signatures characteristic of activated Treg cells (CD4+/CD25+/FOXP3+) and CTLA4+/CD86+ complexes indicative of a tumor-associated immune suppressive phenotype. Strikingly, all lesions showed evidence of TP53 pathway inactivation. Similarly ncRNA and methylation profiles reproduce changes observed post-invasion. Among the most significant findings we observed upregulation of lncRNA HOTAIR in DCIS-C1 lesions and hypermethylation of HOXA5 and specific SOX genes. We conclude that most HG-DCIS lesions, in spite of representing a pre-invasive stage of tumor progression, displayed molecular profiles indistinguishable from invasive breast cancer.
2015-07-25 | GSE69993 | GEO
Project description:DCIS is a non-invasive precursor lesion to invasive breast carcinoma. We still have no understanding on why only some DCIS lesions evolve to invasive cancer while others appear not to do so during the life span of the patient. Here, we performed full exome (tumor vs. matching normal), transcriptome and methylome analysis of 30 pure high-grade DCIS (HG-DCIS) and 10 normal breast epithelial samples. Sixty two percent of HG-DCIS cases displayed mutations affecting cancer driver genes or potential drivers. Mutations were observed affecting PIK3CA (21% of cases), TP53 (17%), GATA3 (7%), MLL3 (7%) and single cases of mutations affecting CDH1, MAP2K4, TBX3, NF1, ATM and ARID1A. Significantly, 83% of lesions displayed numerous large chromosomal copy number alterations, suggesting they might precede selection of cancer driver mutations. Integrated pathway-based modeling analysis of RNA-seq data allowed us to identify two DCIS subgroups (DCIS-C1 and DCIS-C2) based on their tumor intrinsic subtypes, proliferative, immune scores and in the activity of specific signaling pathways. The more aggressive DCIS-C1 (highly proliferative, basal-like or ERBB2+) displayed signatures characteristic of activated Treg cells (CD4+/CD25+/FOXP3+) and CTLA4+/CD86+ complexes indicative of a tumor-associated immune suppressive phenotype. Strikingly, all lesions showed evidence of TP53 pathway inactivation. Similarly ncRNA and methylation profiles reproduce changes observed post-invasion. Among the most significant findings we observed upregulation of lncRNA HOTAIR in DCIS-C1 lesions and hypermethylation of HOXA5 and specific SOX genes. We conclude that most HG-DCIS lesions, in spite of representing a pre-invasive stage of tumor progression, displayed molecular profiles indistinguishable from invasive breast cancer.
2015-07-25 | GSE69240 | GEO
Project description:DCIS is a non-invasive precursor lesion to invasive breast carcinoma. We still have no understanding on why only some DCIS lesions evolve to invasive cancer while others appear not to do so during the life span of the patient. Here, we performed full exome (tumor vs. matching normal), transcriptome and methylome analysis of 30 pure high-grade DCIS (HG-DCIS) and 10 normal breast epithelial samples. Sixty two percent of HG-DCIS cases displayed mutations affecting cancer driver genes or potential drivers. Mutations were observed affecting PIK3CA (21% of cases), TP53 (17%), GATA3 (7%), MLL3 (7%) and single cases of mutations affecting CDH1, MAP2K4, TBX3, NF1, ATM and ARID1A. Significantly, 83% of lesions displayed numerous large chromosomal copy number alterations, suggesting they might precede selection of cancer driver mutations. Integrated pathway-based modeling analysis of RNA-seq data allowed us to identify two DCIS subgroups (DCIS-C1 and DCIS-C2) based on their tumor intrinsic subtypes, proliferative, immune scores and in the activity of specific signaling pathways. The more aggressive DCIS-C1 (highly proliferative, basal-like or ERBB2+) displayed signatures characteristic of activated Treg cells (CD4+/CD25+/FOXP3+) and CTLA4+/CD86+ complexes indicative of a tumor-associated immune suppressive phenotype. Strikingly, all lesions showed evidence of TP53 pathway inactivation. Similarly ncRNA and methylation profiles reproduce changes observed post-invasion. Among the most significant findings we observed upregulation of lncRNA HOTAIR in DCIS-C1 lesions and hypermethylation of HOXA5 and specific SOX genes. We conclude that most HG-DCIS lesions, in spite of representing a pre-invasive stage of tumor progression, displayed molecular profiles indistinguishable from invasive breast cancer. RNAs from 25 out of 30 (83%) pure HG-DCIS and 10 normal breast organoids (total 35 samples) were subjected to RNA-Seq analysis by using Illumina HiSeq2000 platform Please note that description of samples employed for the NGS analyses including age, race, ER/PR immunohistochemistry results, ITIL/STIL scores and PAM50 classification is provided the 'Supplementary Data1_Samples data.xlsx' (available on Superseries record)
2015-07-25 | E-GEOD-69240 | biostudies-arrayexpress