Somatic loss of WWOX is associated with TP53 perturbation in basal-like breast cancer
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE117387 | GEO | 2019/05/17
REPOSITORIES: GEO
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Project description:WWOX expression is lost during tumor progression in many human malignancies including breast cancer. To understand the effects of loss of WWOX expression we analyzed the consequences of its silencing in normal human breast cells (MCF10F). WWOX silencing led to the formation of larger cell colonies, increased cell motility and decreased cell attachment. WWOX silenced cells demonstrated deregulated expression on genes involved in cell cycle, DNA damage response and cell motility. We detected an enrichment of targets activated by the SMAD3 transcription factor. Most notably expression of ANGPTL4, FST, PTHLH and SERPINE1 were all significantly increased upon WWOX silencing. Upregulation of these genes can be reversed by re-expressing WWOX in the previously silenced cells thus suggesting an inverse correlation between WWOX protein expression and SMAD3 transcriptional activity. Importantly, we demonstrate that WWOX physically interacts with SMAD3 protein via WW domain 1, that WWOX expression dramatically decreases SMAD3 occupancy at the ANGPTL4 and SERPINE1 promoters and significantly quenches activation of a TGFβ responsive reporter (3TP-LUX). Furthermore, WWOX expression leads to intracellular redistribution of SMAD3 protein levels redirecting protein availability from the nuclear to the cytoplasmic compartment. Interestingly, meta-analysis of gene expression breast cancer datasets indicate that WWOX and ANGPTL4 expression, encoding a secreted protein of key relevance in breast cancer lung metastatic cells, are inversely correlated and the WWOXlo/ANGPTL4hi cluster of tumors are enriched in triple-negative and basal-like sub-types. In summary, we demonstrate that WWOX modulates SMAD3 signaling in breast cells via direct WW-domain binding and potential cytoplasmic sequestration of SMAD3 protein. Since loss of WWOX expression increases with breast cancer progression and it behaves as an inhibitor of SMAD3 transcriptional activity these observations may help explain, at least in part, the paradoxical pro-tumorigenic effects of TGFβ signaling in advanced breast cancer.
2013-11-28 | GSE47371 | GEO
Project description:WWOX expression is lost during tumor progression in many human malignancies including breast cancer. To understand the effects of loss of WWOX expression we analyzed the consequences of its silencing in normal human breast cells (MCF10F). WWOX silencing led to the formation of larger cell colonies, increased cell motility and decreased cell attachment. WWOX silenced cells demonstrated deregulated expression on genes involved in cell cycle, DNA damage response and cell motility. We detected an enrichment of targets activated by the SMAD3 transcription factor. Most notably expression of ANGPTL4, FST, PTHLH and SERPINE1 were all significantly increased upon WWOX silencing. Upregulation of these genes can be reversed by re-expressing WWOX in the previously silenced cells thus suggesting an inverse correlation between WWOX protein expression and SMAD3 transcriptional activity. Importantly, we demonstrate that WWOX physically interacts with SMAD3 protein via WW domain 1, that WWOX expression dramatically decreases SMAD3 occupancy at the ANGPTL4 and SERPINE1 promoters and significantly quenches activation of a TGFM-NM-2 responsive reporter (3TP-LUX). Furthermore, WWOX expression leads to intracellular redistribution of SMAD3 protein levels redirecting protein availability from the nuclear to the cytoplasmic compartment. Interestingly, meta-analysis of gene expression breast cancer datasets indicate that WWOX and ANGPTL4 expression, encoding a secreted protein of key relevance in breast cancer lung metastatic cells, are inversely correlated and the WWOXlo/ANGPTL4hi cluster of tumors are enriched in triple-negative and basal-like sub-types. In summary, we demonstrate that WWOX modulates SMAD3 signaling in breast cells via direct WW-domain binding and potential cytoplasmic sequestration of SMAD3 protein. Since loss of WWOX expression increases with breast cancer progression and it behaves as an inhibitor of SMAD3 transcriptional activity these observations may help explain, at least in part, the paradoxical pro-tumorigenic effects of TGFM-NM-2 signaling in advanced breast cancer. We compared two independent shRNAs: shWWOX-A and shWWOX-B with 3 biological replicates each one, targeting different regions of the WWOX transcript as a means of ruling out any potential off-target effects.
2013-11-28 | E-GEOD-47371 | biostudies-arrayexpress
Project description:The aim of presented study was to assess the relationship between the presence of estrogen receptor and WWOX gene in breast cancer cell lines.
2020-12-07 | GSE140406 | GEO
Project description:BRCA1 mutation-carriers are predisposed to develop Basal-like breast cancer (BLBC), and p53 mutations are present in the majority of human BLBC cases, suggesting loss of these two tumor suppressors play key roles in development of BLBC. Recent studies suggest that the majority of human breast cancers, including BLBC, may originate from mammary epithelial cells (MECs) in the luminal lineage. However, how loss of p53 and BRCA1 contributes to development of BLBC from luminal MECs remains largely elusive. We developed a novel genetic targeting and lineage tracing approach based on intraductal injection of Cre-expressing adenovirus under the control of the pan-luminal Keratin 8 (K8) promoter (Ad-K8-Cre). We performed intraductal injection of Ad-K8-Cre to female mice carrying conditional knockout alleles of Brca1 and Trp53. The injected females developed mammary tumors within 12 months after injection. Microarray expression profiling of these tumors showed that they most closely resembled human BLBC.
2019-06-27 | GSE114787 | GEO
Project description:BRCA1 mutation-carriers are predisposed to develop Basal-like breast cancer (BLBC), and p53 mutations are present in the majority of human BLBC cases, suggesting loss of these two tumor suppressors play key roles in development of BLBC. Recent studies suggest that the majority of human breast cancers, including BLBC, may originate from mammary epithelial cells (MECs) in the luminal lineage. However, how loss of p53 and BRCA1 contributes to development of BLBC from luminal MECs remains largely elusive. We developed a novel genetic targeting and lineage tracing approach based on intraductal injection of Cre-expressing adenovirus under the control of the pan-luminal Keratin 8 (K8) promoter (Ad-K8-Cre). We performed intraductal injection of Ad-K8-Cre to female mice carrying conditional knockout alleles of Brca1 (Brca1L) and Trp53 (Trp53L). The injected females developed mammary tumors similar to human BLBC within 12 months after injection. Here we characterized MECs targeted by Ad-K8-Cre at different time points after the intraductal injection, as well as mammary tumors developed in this model, by single cell expression analysis.
2019-06-27 | GSE130453 | GEO
Project description:BRCA1 mutation-carriers are predisposed to develop Basal-like breast cancer (BLBC), and p53 mutations are present in the majority of human BLBC cases, suggesting loss of these two tumor suppressors play key roles in development of BLBC. Recent studies suggest that the majority of human breast cancers, including BLBC, may originate from mammary epithelial cells (MECs) in the luminal lineage. However, how loss of p53 and BRCA1 contributes to development of BLBC from luminal MECs remains largely elusive. We developed a novel genetic targeting and lineage tracing approach based on intraductal injection of Cre-expressing adenovirus under the control of the pan-luminal Keratin 8 (K8) promoter (Ad-K8-Cre). We performed intraductal injection of Ad-K8-Cre to female mice carrying conditional knockout alleles of Brca1 (Brca1L) and Trp53 (Trp53L). The injected females developed mammary tumors similar to human BLBC within 12 months after injection. Here we characterized MECs targeted by Ad-K8-Cre one month after the intraductal injection.
2019-06-27 | GSE126761 | GEO
Project description:Abstract BACKGROUND: The basal-like breast cancer (BLBC) subtype is characterized by positive staining for basal mammary epithelial cytokeratin markers, lack of hormone receptor and HER2 expression, and poor prognosis with currently no approved molecularly-targeted therapies. The oncogenic signaling pathways driving basal-like tumorigenesis are not fully elucidated. METHODS: One hundred sixteen unselected breast tumors were subjected to integrated analysis of phosphoinositide 3-kinase (PI3K) pathway related molecular aberrations by immunohistochemistry, mutation analysis, and gene expression profiling. Incidence and relationships between molecular biomarkers were characterized. Findings for select biomarkers were validated in an independent series. Synergistic cell killing in vitro and in vivo tumor therapy was investigated in breast cancer cell lines and mouse xenograft models, respectively. RESULTS: Sixty-four % of cases had an oncogenic alteration to PIK3CA, PTEN, or INPP4B; when including upstream kinases HER2 and EGFR, 75 % of cases had one or more aberration including 97 % of estrogen receptor (ER)-negative tumors. PTEN-loss was significantly associated to stathmin and EGFR overexpression, positivity for the BLBC markers cytokeratin 5/14, and the BLBC molecular subtype by gene expression profiling, informing a potential therapeutic combination targeting these pathways in BLBC. Combination treatment of BLBC cell lines with the EGFR-inhibitor gefitinib plus the PI3K pathway inhibitor LY294002 was synergistic, and correspondingly, in an in vivo BLBC xenograft mouse model, gefitinib plus PI3K-inhibitor PWT-458 was more effective than either monotherapy and caused tumor regression. CONCLUSIONS: Our study emphasizes the importance of PI3K/PTEN pathway activity in ER-negative and basal-like breast cancer and supports the future clinical evaluation of combining EGFR and PI3K pathway inhibitors for the treatment of BLBC. Gene expression profiles were generated for 95 breast tumors using Agilent Human 44K v5 microarrays following the manufacturer protocol. Stratagene Universal Human Reference RNA was used as the common control sample.
2016-08-21 | E-GEOD-74667 | biostudies-arrayexpress
Project description:The WWOX gene is a tumor suppressor probably involved in regulation of cell cycle and apoptosis and downregulated in variety of cancer types.However, its role in colon cancerogenesis is unknown. The aim of this study was to characterize how WWOX may be involved in colon cancerogenesis or cancer progression, how it influences the basic cancer cell features and modifies cell expression profile.Our observations suggest that in HT29 colon cancer cell line increased expression of WWOX may result in transition of cancer cells into more normal- like colon epithelium phenotype, on the other hand in SW480 WWOX revealed the well-known tumour suppressor properties. However, as the colon cancer is very heterogeneous disease, obtained discrepancies may reflect the known differences between cell lines and cancerogenesis pathway, which they undergone. HT29 colon cancer cells were stably transfected with WWOX cDNA. HT29 cells transfected with an empty vector served as a control. Total mRNA was isolated to look for gene-expression differences induced by the WWOX overexpression.
2014-01-23 | E-GEOD-54298 | biostudies-arrayexpress
Project description:The WWOX gene is a tumor suppressor probably involved in regulation of cell cycle and apoptosis and downregulated in variety of cancer types.However, its role in colon cancerogenesis is unknown. The aim of this study was to characterize how WWOX may be involved in colon cancerogenesis or cancer progression, how it influences the basic cancer cell features and modifies cell expression profile.Our observations suggest that in HT29 colon cancer cell line increased expression of WWOX may result in transition of cancer cells into more normal- like colon epithelium phenotype, on the other hand in SW480 WWOX revealed the well-known tumour suppressor properties. However, as the colon cancer is very heterogeneous disease, obtained discrepancies may reflect the known differences between cell lines and cancerogenesis pathway, which they undergone. SW480 colon cancer cells were stably transfected with WWOX cDNA. SW480 cells transfected with an empty vector served as a control. Total mRNA was isolated to look for gene-expression differences induced by the WWOX overexpression.
2014-01-23 | E-GEOD-54299 | biostudies-arrayexpress
Project description:The WWOX gene has been implicated in human cancers, including breast cancer.The development and tumorigenesis between human and mouse mammary glands (MGs) share similar molecular details and signal transduction pathways. We established mouse line that specifically knockout the expression of WWOX gene in the MG epithelial cells (MECs) by crossing BK5-cre mice with our WWOX flox stain. In order to study the gene expression profile in the subpopulation MECs, we isolated the organoids from the 4th MGs of both BK5-cre +; WWOX flox/flox (KO) mice and their WT counterparts (BK5-cre -; WWOX flox/flox), 3 mice each genotype. The total RNA from the mouse MG organoids was extracted and purified by TRIzol/RNeasy Kit and their integrity was checked on Agilent RNA 6000 Nanochip. The goal is to identify the significant perturbation in tumorigenic pathways in these cells induced by WWOX ablation. Mammary gland epithelial organoids samples and gene expression profiles were deribed from three WWOX-KO mice (BK5-cre +; WWOX flox/flox) and from three WWOX-WT mice (BK5-cre -; WWOX flox/flox)
2012-04-14 | E-GEOD-36665 | biostudies-arrayexpress