Lysyl oxidase-like 2 (LOXL2) a new regulator of cell polarity required for metastatic dissemination of basal-like breast carcinomas
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Gema Moreno-Bueno
PROVIDER: E-GEOD-29581 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:The molecular events that mediate the epithelial to mesenchymal transition (EMT) in endometrial cancer remain poorly understood. Using cDNA microarrays, we analyzed a group of endometrial carcinosarcomas (ECS), a true example of EMT in vivo, and we compared their gene expression profiles with those obtained from a group of endometrioid endometrial carcinomas (EEC). The HMGA2 gene (High Mobility Group AT-hook 2), an embryonic nuclear factor that mediates EMT in various tumour models, was among the genes overexpressed in ECS, and HMGA2 overexpression was confirmed in 54% of ECSs by qRT-PCR and immunohistochemistry. Moreover, we found a significant inverse correlation between the expression of HMGA2 and let-7b, a member of the let-7 family of miRNAs that represses HMGA2 expression. These changes were also associated with overexpression of Lin28B, a suppressor of microRNA biogenesis implicated in cancer progression and metastasis. Finally, HMGA2 overexpression, which was detected in less than 3% of EECs, was observed in many non-endometrioid carcinomas (46%). For the first time, we describe a role for HMGA2 in both the process of EMT that contributes to endometrial carcinogenesis and in the acquisition of aggressive phenotypes by this neoplasia. Moreover, we demonstrate changes in the expression of genes modulating processes such as EMT, muscle differentiation, the expression of cancer testis antigens (CTAs) and the immune response. Identification of new molecular markers in endometrial carcinogenesis 15 endometrial carcinosarcomas and 23 endometrioid endometrial carcinoma
2012-11-01 | E-GEOD-33723 | biostudies-arrayexpress
Project description:Cell plasticity is emerging as a key regulator of tumor progression and metastasis. During carcinoma dissemination epithelial cells undergo epithelial to mesenchymal transition (EMT) processes characterized by the acquisition of migratory/invasive properties, while the reverse, mesenchymal to epithelial transition (MET) process, is also essential for metastasis outgrowth. Different transcription factors, called EMT-TFs, including Snail, bHLH and Zeb families are drivers of the EMT branch of epithelial plasticity, and can be post-transcriptionally downregulated by several miRNAs, as the miR-200 family. The specific or redundant role of different EMT-TFs and their functional interrelations are not fully understood. To study the interplay between different EMT-TFs, comprehensive gain and loss-of-function studies of Snail1, Snail2 and/or Zeb1 factors were performed in the prototypical MDCK cell model system. We here describe that Snail1 and Zeb1 are mutually required for EMT induction while continuous Snail1 and Snail2 expression, but not Zeb1, is needed for maintenance of the mesenchymal phenotype in MDCK cells. In this model system, EMT is coordinated by Snail1 and Zeb1 through transcriptional and epigenetic downregulation of the miR-200 family. Interestingly, Snail1 is involved in epigenetic CpG DNA methylation of the miR-200 loci, essential to maintain the mesenchymal phenotype. The present results thus define a novel functional interplay between Snail and Zeb EMT-TFs in miR200f regulation providing a molecular link to their previous involvement in the generation of EMT process in vivo. Expression analysis of MDCK over-expression EMT-TF Analysis of 7 overexpression MDCK cells each of them using biological rpelicates (MDCK-E47, Snail2, Snail1, Twist1, Tiwst2, Zeb1, Zeb2)
2014-09-09 | E-GEOD-61217 | biostudies-arrayexpress
Project description:Basal-like breast carcinoma is characterized by the expression of basal/myoepithelial markers, undifferentiated phenotype, highly aggressive behaviour and a frequent triple negative status (ESR-, PR-, Her2neu-). We have previously shown that epithelial-mesenchymal transition (EMT) occurs in basal-like breast tumours and identified Lysyl- Oxidase-Like 2 (LOXL2) as an EMT player and a poor prognosis marker in squamous cell carcinomas. We now show that LOXL2 mRNA is overexpressed in basal-like human breast carcinomas. Identification of new molecular markers in basal breast carcinomas
2011-10-21 | GSE29581 | GEO
Project description:Epithelial-to-Mesenchymal Transition (EMT) is a key process contributing to the aggressiveness of cancer cells. EMT is triggered by activation of different transcription factors collectively known as EMT-TFs. Different cellular cues and cell signalling networks activate EMT at transcriptional and posttranscriptional level in different biological and pathological situations. Among them, overexpression of LOXL2 (lysyl oxidase-like 2) induces EMT independent of its catalytic activity. Remarkably, perinuclear/cytoplasmic accumulation of LOXL2 is a poor prognosis marker of squamous cell carcinomas and is associated to basal breast cancer metastasis by mechanisms no yet fully understood. Here, we report that overexpression of LOXL2 promotes its accumulation in the Endoplasmic Reticulum where it interacts with HSPA5 leading to activation of the IRE1-XBP1-branch of the Unfolded Protein Response (UPR). LOXL2-dependent UPR activation induces the expression of several EMT-TFs: SNAI1, SNAI2, ZEB2 and TCF3 that are direct transcriptional targets of XBP1. Remarkably, inhibition of IRE1 blocks LOXL2-dependent upregulation of EMT-TFs thus hindering EMT induction. LOXL2 relationship to Endoplasmic Reticulum Stress
2017-05-11 | GSE90605 | GEO
Project description:Squamous cell lung cancer (SCC) and adenocarcinoma are the most common subtypes of the lung tumours. The search for cancer-directed treatments has increased the need for understanding molecular features of either histological subtype. The aim of this study was to identify transcriptional regulation differences due to miRNA expression profiles between SCC and adenocarcinoma. For this propose, a total of 44 patients were evaluated to assess the correlation between the miRNA and messenger RNA (mRNA) expression levels. Total RNA were isolated, amplified, labeled and hybridized on Agilent human whole genome V2 22 K microarray chip. qRT-PCR was conducted to validate our microarray data. MicroRNA expression was detected and quantified using the TaqMan Low Density Arrays. Predicted miRNA-mRNA interactions were taken from miRanda, miRWalk and TargetScan. After processing data, changes in 56 mRNAs as well as in 9 miRNAs were detected between SCC and adenocarcinoma. Nearly 20% of overall deregulated genes were targeted by at least one of the 9 miRNAs (miR-149, miR-205, miR-375, miR-378, miR-422a, miR-483-5p, miR-494, miR-601 and miR-708) differentially expressed between SCC and adenocarcinoma. Genes predicted (CEACAM6, CGN, CLDN3, ABCC3, MLPH, ACSL5, TMEM45B, MUC1) to be targeted by several miRNAs were individually validated by qRT-PCR. We found genes involved in tight junctions and other involved in resistance to anticancer agents. These genes were reliable biomarkers, with high sensitivity and specificity, to detect differences between the two most common histological subtypes of lung cancer. In conclusion, our data demonstrate that the transcriptional regulation differences through miRNA expression play an important role in key hallmarks of non-small cell lung cancer. Identification of new molecular markers in lung carcinoma 44 tumour samples following surgical resection for clinical early stage NSCLC (SCC and adenocarcinoma) This series represents the mRNA profiling only (not miRNA). The related miRNA data are in Series GSE43000.
2013-12-10 | E-GEOD-42998 | biostudies-arrayexpress
Project description:Title: CAMK1D amplification implicated in epithelial-mesenchymal transition in basal-like breast cancer Summary: Breast cancer exhibits clinical and molecular heterogeneity, where expression-profiling studies have identified five major molecular subtypes. The basal-like subtype, expressing basal epithelial markers and negative for estrogen receptor (ER), progesterone receptor (PR) and HER2, is associated with higher overall levels of DNA copy number alteration (CNA), specific CNAs (like gain on chromosome 10p), and poor prognosis. Discovering the molecular genetic basis of tumor subtypes may provide new opportunities for therapy. To identify the driver oncogene on 10p associated with basal-like tumors, we analyzed genomic profiles of 172 breast carcinomas. The smallest shared region of gain spanned just seven genes at 10p13, including calcium/calmodulin-dependent protein kinase ID (CAMK1D), functioning in intracellular signaling but not previously linked to cancer. By microarray, CAMK1D was overexpressed when amplified, and by immunohistochemistry exhibited elevated expression in invasive carcinomas compared to carcinoma in situ. Engineered overexpression of CAMK1D in non-tumorigenic breast epithelial cells led to increased cell proliferation, and molecular and phenotypic alterations indicative of epithelial-mesenchymal transition (EMT), including loss of cell-cell adhesions and increased cell migration and invasion. Our findings identify CAMK1D as a novel amplified oncogene linked to EMT in breast cancer, and as a potential therapeutic target with particular relevance to clinically unfavorable basal-like tumors.
2009-09-08 | GSE12811 | GEO
Project description:Title: CAMK1D amplification implicated in epithelial-mesenchymal transition in basal-like breast cancer Summary: Breast cancer exhibits clinical and molecular heterogeneity, where expression-profiling studies have identified five major molecular subtypes. The basal-like subtype, expressing basal epithelial markers and negative for estrogen receptor (ER), progesterone receptor (PR) and HER2, is associated with higher overall levels of DNA copy number alteration (CNA), specific CNAs (like gain on chromosome 10p), and poor prognosis. Discovering the molecular genetic basis of tumor subtypes may provide new opportunities for therapy. To identify the driver oncogene on 10p associated with basal-like tumors, we analyzed genomic profiles of 172 breast carcinomas. The smallest shared region of gain spanned just seven genes at 10p13, including calcium/calmodulin-dependent protein kinase ID (CAMK1D), functioning in intracellular signaling but not previously linked to cancer. By microarray, CAMK1D was overexpressed when amplified, and by immunohistochemistry exhibited elevated expression in invasive carcinomas compared to carcinoma in situ. Engineered overexpression of CAMK1D in non-tumorigenic breast epithelial cells led to increased cell proliferation, and molecular and phenotypic alterations indicative of epithelial-mesenchymal transition (EMT), including loss of cell-cell adhesions and increased cell migration and invasion. Our findings identify CAMK1D as a novel amplified oncogene linked to EMT in breast cancer, and as a potential therapeutic target with particular relevance to clinically unfavorable basal-like tumors.
2009-09-08 | GSE12813 | GEO
Project description:Title: CAMK1D amplification implicated in epithelial-mesenchymal transition in basal-like breast cancer Summary: Breast cancer exhibits clinical and molecular heterogeneity, where expression-profiling studies have identified five major molecular subtypes. The basal-like subtype, expressing basal epithelial markers and negative for estrogen receptor (ER), progesterone receptor (PR) and HER2, is associated with higher overall levels of DNA copy number alteration (CNA), specific CNAs (like gain on chromosome 10p), and poor prognosis. Discovering the molecular genetic basis of tumor subtypes may provide new opportunities for therapy. To identify the driver oncogene on 10p associated with basal-like tumors, we analyzed genomic profiles of 172 breast carcinomas. The smallest shared region of gain spanned just seven genes at 10p13, including calcium/calmodulin-dependent protein kinase ID (CAMK1D), functioning in intracellular signaling but not previously linked to cancer. By microarray, CAMK1D was overexpressed when amplified, and by immunohistochemistry exhibited elevated expression in invasive carcinomas compared to carcinoma in situ. Engineered overexpression of CAMK1D in non-tumorigenic breast epithelial cells led to increased cell proliferation, and molecular and phenotypic alterations indicative of epithelial-mesenchymal transition (EMT), including loss of cell-cell adhesions and increased cell migration and invasion. Our findings identify CAMK1D as a novel amplified oncogene linked to EMT in breast cancer, and as a potential therapeutic target with particular relevance to clinically unfavorable basal-like tumors. Overall design: HEEBO oligonucleotide microarrays from the Stanford Functional Genomics Facility were used to perform gene expression profiling of four CAMK1D or control-transfected MCF10A breast epithelial cell line derivatives, in comparison to a universal RNA reference. Gene set enrichment analysis was used to identify CAMK1D-assocatied gene sets. Set of arrays that are part of repeated experiments Cell Line: CAMK1D or vector transfected MCF10A breast epithelial cell line derivatives Biological Replicate Computed
2010-06-24 | E-GEOD-12811 | biostudies-arrayexpress
Project description:Spontaneously occurring canine mammary cancer (MC) represents an excellent model of human breast cancer, but is greatly understudied. We performed high density arrays on 12 canine MC cases, including 7 simple carcinomas and four complex carcinomas. Simple carcinomas, which histologically match human breast carcinomas, harbor extensive genomic aberrations, many faithfully recapitulating key features of human breast cancer. Complex carcinomas, with luminal and myoepithelial cells both proliferating (which is rare in human breast cancer), appear to lack genomic abnormalities. Comparison of CNAs from canine mammary simple carcinomas and complex carcinomas
2014-09-07 | E-GEOD-54535 | biostudies-arrayexpress
Project description:Title: CAMK1D amplification implicated in epithelial-mesenchymal transition in basal-like breast cancer Summary: Breast cancer exhibits clinical and molecular heterogeneity, where expression-profiling studies have identified five major molecular subtypes. The basal-like subtype, expressing basal epithelial markers and negative for estrogen receptor (ER), progesterone receptor (PR) and HER2, is associated with higher overall levels of DNA copy number alteration (CNA), specific CNAs (like gain on chromosome 10p), and poor prognosis. Discovering the molecular genetic basis of tumor subtypes may provide new opportunities for therapy. To identify the driver oncogene on 10p associated with basal-like tumors, we analyzed genomic profiles of 172 breast carcinomas. The smallest shared region of gain spanned just seven genes at 10p13, including calcium/calmodulin-dependent protein kinase ID (CAMK1D), functioning in intracellular signaling but not previously linked to cancer. By microarray, CAMK1D was overexpressed when amplified, and by immunohistochemistry exhibited elevated expression in invasive carcinomas compared to carcinoma in situ. Engineered overexpression of CAMK1D in non-tumorigenic breast epithelial cells led to increased cell proliferation, and molecular and phenotypic alterations indicative of epithelial-mesenchymal transition (EMT), including loss of cell-cell adhesions and increased cell migration and invasion. Our findings identify CAMK1D as a novel amplified oncogene linked to EMT in breast cancer, and as a potential therapeutic target with particular relevance to clinically unfavorable basal-like tumors. Overall design: cDNA microarrays from the Stanford Functional Genomics Facility were used to carry out array-based Comparative Genomic Hybridization (array CGH) analysis of 172 human breast tumor specimens, in comparison to normal female DNA. Map positions for arrayed cDNA clones were assigned using the NCBI genome assembly, accessed through the UCSC genome browser database (NCBI Build 36). The CLuster Along Chromosomes (CLAC) method was used to call DNA gains and losses. Set of arrays that are part of repeated experiments Keywords: Biological Replicate Biological Replicate Computed
2010-06-24 | E-GEOD-12813 | biostudies-arrayexpress