MRNA sequencing of breast cancer brain metastasis tumors FACS sorted for E-cadherin high and low levels
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE199775 | GEO | 2022/07/15
REPOSITORIES: GEO
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Project description:mRNA sequencing of breast cancer brain metastasis tumors FACS sorted for E-cadherin high and low levels
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Project description:The loss of E-cadherin causes dysfunction of the cell-cell junction machinery, which is an initial step in epithelial-to-mesenchymal transition (EMT), facilitating cancer cell invasion and the formation of metastases. A set of transcriptional repressors of E-cadherin (CDH1) gene expression, including Snail1, Snail2 and Zeb2 mediate E-cadherin down-regulation in breast cancer. However, the molecular mechanisms underlying the control of E-cadherin expression in breast cancer progression remain largely unknown. Here, by using global gene expression approaches, we uncover a novel function for Cdc42 GTPase-activating protein (CdGAP) in the regulation of expression of genes involved in EMT. We found that CdGAP used its proline-rich domain to form a functional complex with Zeb2 to mediate the repression of E-cadherin expression in ErbB2-transformed breast cancer cells. Conversely, knockdown of CdGAP expression led to a decrease of the transcriptional repressors Snail1 and Zeb2, and this correlated with an increase in E-cadherin levels, restoration of cell-cell junctions, and epithelial-like morphological changes. In vivo, loss of CdGAP in ErbB2-transformed breast cancer cells impaired tumor growth and suppressed metastasis to lungs. Finally, CdGAP was highly expressed in basal-type breast cancer cells, and its strong expression correlated with poor prognosis in breast cancer patients. Together, these data support a previously unknown nuclear function for CdGAP where it cooperates in a GAP-independent manner with transcriptional repressors to function as a critical modulator of breast cancer through repression of E-cadherin transcription. Targeting Zeb2-CdGAP interactions may represent novel therapeutic opportunities for breast cancer treatment.
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Project description:The loss of E-cadherin causes dysfunction of the cell-cell junction machinery, which is an initial step in epithelial-to-mesenchymal transition (EMT), facilitating cancer cell invasion and the formation of metastases. A set of transcriptional repressors of E-cadherin (CDH1) gene expression, including Snail1, Snail2 and Zeb2 mediate E-cadherin down-regulation in breast cancer. However, the molecular mechanisms underlying the control of E-cadherin expression in breast cancer progression remain largely unknown. Here, by using global gene expression approaches, we uncover a novel function for Cdc42 GTPase-activating protein (CdGAP) in the regulation of expression of genes involved in EMT. We found that CdGAP used its proline-rich domain to form a functional complex with Zeb2 to mediate the repression of E-cadherin expression in ErbB2-transformed breast cancer cells. Conversely, knockdown of CdGAP expression led to a decrease of the transcriptional repressors Snail1 and Zeb2, and this correlated with an increase in E-cadherin levels, restoration of cell-cell junctions, and epithelial-like morphological changes. In vivo, loss of CdGAP in ErbB2-transformed breast cancer cells impaired tumor growth and suppressed metastasis to lungs. Finally, CdGAP was highly expressed in basal-type breast cancer cells, and its strong expression correlated with poor prognosis in breast cancer patients. Together, these data support a previously unknown nuclear function for CdGAP where it cooperates in a GAP-independent manner with transcriptional repressors to function as a critical modulator of breast cancer through repression of E-cadherin transcription. Targeting Zeb2-CdGAP interactions may represent novel therapeutic opportunities for breast cancer treatment.
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Project description:Alterations in the cadherin-catenin adhesion complexes are involved in tumor initiation, progression and metastasis. However, the functional implication of distinct cadherin types in breast cancer biology is still poorly understood. Methods: To compare the functional role of E-cadherin and P-cadherin in invasive breast cancer, we stably transfected these molecules into the MDA-MB-231 cell line, and investigated their effects on motility, invasion and gene expression regulation. Expression of either E- and P-cadherin significantly increased cell aggregation and induced a switch from fibroblastic to epithelial morphology. Although expression of these cadherins did not completely reverse the mesenchymal phenotype of MDA-MB-231 cells, both E- and P-cadherin decreased fibroblast-like migration and invasion through extracellular matrix in a similar way. Moreover, microarray gene expression analysis of MDA-MB-231 cells after expression of E- and P-cadherins revealed that these molecules can activate signaling pathways leading to significant changes in gene expression. Although the expression patterns induced by E- and P-cadherin showed more similarities than differences, 40 genes were differentially modified by the expression of either cadherin type.
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Project description:Oct4, a key transcription factor for maintaining the pluripotency and self-renewal of stem cells has been reported previously. It also plays an important role in tumor proliferation and apoptosis, but the role of Oct4 been in tumor metastasis is still not very clear. Here, we found that ectopic expression of Oct4 in breast cancer cells can inhibit their migration and invasion. Detailed examinations revealed that Oct4 up-regulates expression of E-cadherin, indicative of its inhibitory role in epithelial-mesenchymal transition (EMT). RNA-sequence assay showed that Oct4 down-regulates expression of Rnd1. As an atypical Rho protein, Rnd1 can affect cytoskeleton rearrangement and regulate cadherin-based cell-cell adhesion by antagonizing the typical Rho protein, RhoA. Ectopic expression of Rnd1 in MDA-MB-231 cells changes cell morphology which influences cell adhesion and increases migration. It is reported that EMT is accompanied by cytoskeleton remodeling, we hypothesized that Rnd1 may play a role in regulating EMT. Over-expression of Rnd1 can partly rescue the inhibitory effects induced by Oct4, not only migration and invasion, but also in E-cadherin level and cellular morphology. Furthermore, silencing of Rnd1 can up-regulate the expression of E-cadherin in MDA-MB-231 cells. These results present evidence that ectopic expression of Oct4 increases E-cadherin and inhibits metastasis, effects which may be related to Rnd1 associated cell-cell adhesion in breast cancer cells. Examination of mRNA profiles in MDA-MB-231 cells with OCT4 overexpressing
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Project description:E-cadherin suppresses invasion and promotes metastasis in multiple breast cancer models
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Project description:Lung cancer is the leading cause of cancer death worldwide. Brain metastasis is a major cause of morbidity and mortality in lung cancer. CDH2 (N-cadherin, a mesenchymal marker in epithelial-mesenchymal transition) and ADAM9 (a member of type I transmembrane proteins) have been reported relating to lung cancer brain metastasis, however, it is still not clear whether any interaction between them to mediate lung cancer brain metastasis. Since microRNAs were discovered to regulate many biological functions and disease processes (e.g., cancer) by down-regulating their target genes, microRNA microarrays were used to identify ADAM9 regulated miRNAs that target CDH2 in aggressive lung cancer cells. Luciferase assays and immunoblotting proved that CDH2 was a target gene of miR-218. The expression of miR-218 was generated from pri-mir-218-1, located in SLIT2, in low invasive lung adenocarcinoma while it was inhibited in aggressive lung adenocarcinoma. Down-regulation of ADAM9 could up-regulate SLIT2 and miR-218, thus down-regulate CDH2 expression. This study elucidated the mechanism of ADAM9 activating CDH2 may be due to release the inhibition of miR-218 on CDH2 in lung adenocarcinoma. For each of the cell lines bm#2, bm#7, and F4, one microarray was analyzed.
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Project description:Lung cancer is the leading cause of cancer death worldwide. Brain metastasis is a major cause of morbidity and mortality in lung cancer. CDH2 (N-cadherin, a mesenchymal marker in epithelial-mesenchymal transition) and ADAM9 (a member of type I transmembrane proteins) have been reported relating to lung cancer brain metastasis, however, it is still not clear whether any interaction between them to mediate lung cancer brain metastasis. Since microRNAs were discovered to regulate many biological functions and disease processes (e.g., cancer) by down-regulating their target genes, microRNA microarrays were used to identify ADAM9 regulated miRNAs that target CDH2 in aggressive lung cancer cells. Luciferase assays and immunoblotting proved that CDH2 was a target gene of miR-218. The expression of miR-218 was generated from pri-mir-218-1, located in SLIT2, in low invasive lung adenocarcinoma while it was inhibited in aggressive lung adenocarcinoma. Down-regulation of ADAM9 could up-regulate SLIT2 and miR-218, thus down-regulate CDH2 expression. This study elucidated the mechanism of ADAM9 activating CDH2 may be due to release the inhibition of miR-218 on CDH2 in lung adenocarcinoma. For each of the cell lines bm#2, bm#7, and F4, one microarray was analyzed.
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