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Investigation of breast cancer-associated mutations in RND1 gene

ABSTRACT: We identified the Rho family GTPase Rnd1 as a candidate breast tumor suppressor by using bioinformatics analysis in conjunction with iRNA silencing. Upon silencing of Rnd1, normal mammary epithelial cells underwent a complete EMT but eventually became senescent, suggesting that they had experienced an oncogenic insult. Expression of c-Myc rescued the Rnd1-depleted cells from senescence by suppressing p27Kip and it enabled their neoplastic conversion. The resulting cells were able to grow in soft agar and to form invasive, multi-acinar structures in 3D Matrigel. Silencing of Rnd1 promoted disruption of epithelial adhesion and polarity in xenograft models. In contrast, expression of Rnd1 inhibited tumor development. Mechanistic studies revealed that Rnd1 suppresses Ras signaling and prevents the EMT by activating the Ras-GAP domain of Plexin B1. Finally, analysis of clinical samples and cancer cell lines provided evidence that gene deletion, epigenetic silencing, and missense mutations contribute to inactivate RND1 in a subset of human breast cancers. These results indicate that Rnd1 promotes epithelial adhesion and polarity and suppresses oncogenesis by restraining unscheduled activation of Ras.

ORGANISM(S): Homo sapiens

PROVIDER: GSE43828 | GEO | 2014/01/01

SECONDARY ACCESSION(S): PRJNA188274

REPOSITORIES: GEO

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Investigation of breast cancer-associated mutations in RND1 gene

Project description:We identified the Rho family GTPase Rnd1 as a candidate breast tumor suppressor by using bioinformatics analysis in conjunction with iRNA silencing. Upon silencing of Rnd1, normal mammary epithelial cells underwent a complete EMT but eventually became senescent, suggesting that they had experienced an oncogenic insult. Expression of c-Myc rescued the Rnd1-depleted cells from senescence by suppressing p27Kip and it enabled their neoplastic conversion. The resulting cells were able to grow in soft agar and to form invasive, multi-acinar structures in 3D Matrigel. Silencing of Rnd1 promoted disruption of epithelial adhesion and polarity in xenograft models. In contrast, expression of Rnd1 inhibited tumor development. Mechanistic studies revealed that Rnd1 suppresses Ras signaling and prevents the EMT by activating the Ras-GAP domain of Plexin B1. Finally, analysis of clinical samples and cancer cell lines provided evidence that gene deletion, epigenetic silencing, and missense mutations contribute to inactivate RND1 in a subset of human breast cancers. These results indicate that Rnd1 promotes epithelial adhesion and polarity and suppresses oncogenesis by restraining unscheduled activation of Ras. genomic DNA from 96 breast cancer tissues and 8 normal mammary tissues were extracted and subjected to SOLID deep sequencing for exons of the RND1 gene to identify tumor-associated mutations with the amino acid exchanges There were two separate SOLID runs (0136 and 0270), on the same 96 tumors. The pools are indicated by "A1", "A2", "B1", etc.

2014-01-01 | E-GEOD-43828 | biostudies-arrayexpress

Oct4 affects E-cadherin expression via regulating Rnd1 associated cytoskeleton rearrangement in breast cancer cells

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

2014-01-25 | E-GEOD-54392 | biostudies-arrayexpress

Oct4 affects E-cadherin expression via regulating Rnd1 associated cytoskeleton rearrangement in breast cancer cells

2014-01-25 | GSE54392 | GEO

Innate immune role of Rnd1 during H5N1 infection

Project description:Intracellular and cell surface molecules are an essential part of the innate immune system. We describe a novel cellular defense mechanism based upon a membrane-associated protein RND1. RND1 belongs to the Rho GTPase family, but unlike other members, it is constitutively active. We show that RND1 is induced by pro-inflammatory cytokines during viral and bacterial infections and provides protection against these pathogens through two distinct mechanisms.

2022-06-21 | GSE185216 | GEO

Gene profile from RND1-knock down in MDF10A cells

Project description:Microarray analysis was performed to get gene expression profiles induced by knock-down RND1 gene in MCF10A cells total RNA extracted from MCF10A cells carrying either sh-RNA targetting RND1 gene (sh-34 or sh-35) or scramble control were subjected to Microarray analysis

2014-01-01 | E-GEOD-43885 | biostudies-arrayexpress

Gene profile from RND1-knock down in MDF10A cells

Project description:Microarray analysis was performed to get gene expression profiles induced by knock-down RND1 gene in MCF10A cells

2014-01-01 | GSE43885 | GEO

Deciphering the direct transcriptional targets of the Drosophila Activating transcription factor 3 (Atf3) via ChIp-seq: Atf3 bridges the gap between cell polarity and the nucleus

Project description:Epithelial structure and function are governed by evolutionarily conserved signaling programs. The Drosophila Activating transcription factor 3 (Atf3) prevents epithelial cell replacement during abdominal morphogenesis, yet its transcriptional targets are unknown. Here we demonstrate that Atf3 positively and negatively regulates target genes central to cytoskeleton dynamics and adhesion. Epithelial clones overexpressing Atf3 are enriched for basolateral proteins at the expense of apical identity. Strikingly, Atf3 functions downstream of the Scrib polarity module. Depleting either scrib or dlg1 induces atf3 expression, while loss of atf3 suppresses differentiation and polarity defects in cells deficient for the Scrib complex

2018-02-20 | GSE71206 | GEO

Addition of RND1 peptide to E. coli BW25113 DELserB, his operator to lacZ transcription fusion.

Project description:Addition of RND1 peptide to E. coli BW25113 (DELserB, his operator to lacZ transcription fusion.

2022-03-31 | PXD014049 | Pride

Notch signaling rapidly regulates the expression of the small GTPase RND1 and a diverse endothelial transcriptome

Project description:Endothelial Notch signaling regulates transcription of many downstream effectors controlling sprouting, migration, proliferation, barrier formation, and other phenotypes. However, endothelial-relevant Notch targets are largely uncharacterized. Few are studied in depth, and many transient, early response Notch targets are yet to be described. We therefore determined the Notch early response transcriptional profile in several experimentally relevant in vivo and in vitro contexts: ligand-specific or EGTA-induced Notch activation in different primary endothelial cells, and gamma secretase-mediated Notch inhibition in neonatal brain endothelium in a RiboTag mouse model. The intersection of these profiles reveals a core set of early Notch-responsive targets. Among these are effectors in GPCR signaling, not previously implicated downstream of Notch signaling. We demonstrate the Rho GTPase RND1 is a direct Notch transcriptional target and required for Notch control of sprouting angiogenesis, endothelial migration and Ras activity.

2022-01-11 | GSE163568 | GEO

Gene expression profiles of p53 depleted human mammary epithelial cells with their Ras-infected epithelial and mesenchymal derivatives

Project description:The epithelial-mesenchymal transition (EMT) is an embryonic transdiffrentiation program which consists of the conversion of polarized epithelial cells into a motile mesenchymal phenotype. EMT is aberrantly reactivated during tumor progression, promoting metastatic dissemination. Herein, we demonstrate that EMT permissive conditions also favor tumor initiation by minimizing the number of events required for neoplastic transformation. We further demonstrated that even partial commitment of human mammary epithelial cells into an EMT program is sufficient to confer malignant properties, suggesting that the reactivation of embryonic EMT inducers participate to the primary tumor growth long before the initiation of the invasion-metastasis cascade. Human mammary epithelial cells (HMEC) were sequentially depleted in p53 through RNA interference (shp53), transduced with H-RasG12V and immortalized by hTert. Two different Tert/shp53/Ras cell population emerge that display either an epithelial (Epi) or a mesenchymal (Mes) phenotype. Gene expression profiles of the Tert/shp53 control cells and of tert/shp53/Ras/Epi and Tert/shp53/Ras/Mes were analyzed.

2012-01-31 | E-GEOD-26541 | biostudies-arrayexpress

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