Nck deficiency is associated with delayed breast carcinoma progression and reduced metastasis

Morris, Dan; Popp, Julia; Tang, Leung K.; Gibbs, Holly C.; Schmitt, Emily E.; Chaki, Sankar P.; Bywaters, Briana C.; Yeh, Alvin T.; Porter, Weston W.; Burghardt, Robert C.; Barhoumi, Rola; Rivera, Gonzalo

doi:10.1091/mbc.e17-02-0106

Cited by 18 publications

(18 citation statements)

References 105 publications

(125 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Podosomes are rich in MMPs that drive matrix remodeling in various cell types . In a recent study, using human breast carcinoma cell line MDA‐MB‐231 and mouse model, we demonstrated that Nck facilitates MMP14‐mediated breast carcinoma cell invasion . In our present study, RT_PCR analysis revealed high MMP14 expression in MDA‐MB‐231 cells compared with noncancerous cells MCF‐10 and HUVEC (Figure B).…”

Section: Discussionsupporting

confidence: 67%

“…71 In a recent study, using human breast carcinoma cell line MDA-MB-231 and mouse model, we demonstrated that Nck facilitates MMP14-mediated breast carcinoma cell invasion. 12 In our present study, RT_PCR analysis revealed high MMP14 expression in MDA-MB-231 cells compared with noncancerous cells MCF-10 and HUVEC ( Figure 5B). Other metalloproteases like ADAMs play roles in mediating cell-cell and cell-matrix interactions in both normal development and pathological states such as Alzheimer's disease, arthritis, cancer, and cardiac hypertrophy.…”

Section: Discussionsupporting

confidence: 60%

“…Cancer metastasis is a condition which requires ECM degradation and cellular invasion. Earlier, we and others have shown the involvement of Nck actin regulator in tumorigenesis and metastasis . This study emphasizes the role of Nck in podosome biogenesis and podosome‐mediated ECM degradation, which is necessary for cancer cell invasion.…”

Section: Introductionsupporting

confidence: 66%

“…Earlier, we and others have shown the involvement of Nck actin regulator in tumorigenesis and metastasis. [12][13][14] This study emphasizes the role of Nck in podosome biogenesis and podosome-mediated ECM degradation, which is necessary for cancer cell invasion. Nck initiates actin polymerization in invadopodia through the activation of N-WASp/Arp 2/3 pathway in cancer cells.…”

Section: Introductionmentioning

confidence: 83%

See 3 more Smart Citations

Nck adapter proteins promote podosome biogenesis facilitating extracellular matrix degradation and cancer invasion

2019

Self Cite

View full text Add to dashboard Cite

BackgroundPodosomes are membrane‐bound adhesive structures formed by actin remodeling. They are capable of extracellular matrix (ECM) degradation, which is a prerequisite for cancer cell invasion and metastasis. The signaling mechanism of podosome formation is still unknown in cancer. We previously reported that Nck adaptors regulate directional cell migration and endothelial lumen formation by actin remodeling, while deficiency of Nck reduces cancer metastasis. This study evaluated the role of Nck adaptors in podosome biogenesis and cancer invasion.MethodsThis study was conducted in vitro using both healthy cells (Human Umbilical Vein Endothelial Cell, 3T3 fibroblasts) and cancer cells (prostate cancer cell line; PC3, breast cancer cell line; MDA‐MB‐231). Confocal and TIRF imaging of cells expressing Green Fluorescence Protein (GFP) mutant under altered levels of Nck or downstream of kinase 1 (Dok1) was used to evaluate the podosome formation and fluorescent gelatin matrix degradation. Levels of Nck in human breast carcinoma tissue sections were detected by immune histochemistry using Nck polyclonal antibody. Biochemical interaction of Nck/Dok1 was detected in podosome forming cells using immune precipitation and far‐western blotting.ResultsThis study demonstrates that ectopic expression of Nck1 and Nck2 can induce the endothelial podosome formation in vitro. Nck silencing by short‐hairpin RNA blocked podosome biogenesis and ECM degradation in cSrc‐Y530F transformed endothelial cells in this study. Immunohistochemical analysis revealed the Nck overexpression in human breast carcinoma tissue sections. Immunoprecipitation and far‐western blotting revealed the biochemical interaction of Nck/p62Dok in podosome forming cells.ConclusionsNck adaptors in interaction with Dok1 induce podosome biogenesis and ECM degradation facilitating cancer cell invasion, and therefore a bona fide target of cancer therapy.

show abstract

Section: Discussionsupporting

confidence: 67%

Section: Discussionsupporting

confidence: 60%

Section: Introductionsupporting

confidence: 66%

Section: Introductionmentioning

confidence: 83%

See 2 more Smart Citations

Nck adapter proteins promote podosome biogenesis facilitating extracellular matrix degradation and cancer invasion

2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…NCK1 is an tyrosine kinase that regulation cell adhesion and has role in breast carcinoma cell invasion and metastasis 44 . CBL over-expression results in inhibition of transforming growth factor tumor suppressor activity and breast cancer prognosis 45 .…”

Section: T-sne (T-distributed Stochastic Neighbour Embedding) T-sne mentioning

confidence: 99%

Classification models for Invasive Ductal Carcinoma Progression, based on gene expression data-trained supervised machine learning

Roy

Kumar

Mittal

et al. 2020

Sci Rep

View full text Add to dashboard Cite

Early detection of breast cancer and its correct stage determination are important for prognosis and rendering appropriate personalized clinical treatment to breast cancer patients. However, despite considerable efforts and progress, there is a need to identify the specific genomic factors responsible for, or accompanying Invasive Ductal Carcinoma (IDC) progression stages, which can aid the determination of the correct cancer stages. We have developed two-class machine-learning classification models to differentiate the early and late stages of IDC. The prediction models are trained with RNA-seq gene expression profiles representing different IDC stages of 610 patients, obtained from The Cancer Genome Atlas (TCGA). Different supervised learning algorithms were trained and evaluated with an enriched model learning, facilitated by different feature selection methods. We also developed a machinelearning classifier trained on the same datasets with training sets reduced data corresponding to IDC driver genes. Based on these two classifiers, we have developed a web-server Duct-BRCA-CSP to predict early stage from late stages of IDC based on input RNA-seq gene expression profiles. The analysis conducted by us also enables deeper insights into the stage-dependent molecular events accompanying IDC progression. The server is publicly available at http://bioinfo.icgeb.res.in/duct-BRCA-CSP.

show abstract

Distinct Requirements for Adaptor Proteins NCK1 and NCK2 in Mammary Gland Development

Golding,

Ferrier,

New

et al. 2023

J Mammary Gland Biol Neoplasia

View full text Add to dashboard Cite

The adaptor proteins NCK1 and NCK2 are well-established signalling nodes that regulate diverse biological processes including cell proliferation and actin dynamics in many tissue types. Here we have investigated the distribution and function of Nck1 and Nck2 in the developing mouse mammary gland. Using publicly available single-cell RNA sequencing data, we uncovered distinct expression profiles between the two paralogs. Nck1 showed widespread expression in luminal, basal, stromal and endothelial cells, while Nck2 was restricted to luminal and basal cells, with prominent enrichment in hormone-sensing luminal subtypes. Next, using mice with global knockout of Nck1 or Nck2, we assessed mammary gland development during and after puberty (5, 8 and 12 weeks of age). Mice lacking Nck1 or Nck2 displayed significant defects in ductal outgrowth and branching at 5 weeks compared to controls, and the defects persisted in Nck2 knockout mice at 8 weeks before normalizing at 12 weeks. These defects were accompanied by an increase in epithelial cell proliferation at 5 weeks and a decrease at 8 weeks in both Nck1 and Nck2 knockout mice. We also profiled expression of several key genes associated with mammary gland development at these timepoints and detected temporal changes in transcript levels of hormone receptors as well as effectors of cell proliferation and migration in Nck1 and Nck2 knockout mice, in line with the distinct phenotypes observed at 5 and 8 weeks. Together these studies reveal a requirement for NCK proteins in mammary gland morphogenesis, and suggest that deregulation of Nck expression could drive breast cancer progression and metastasis.

show abstract

Nck deficiency is associated with delayed breast carcinoma progression and reduced metastasis

Cited by 18 publications

References 105 publications

Nck adapter proteins promote podosome biogenesis facilitating extracellular matrix degradation and cancer invasion

Nck adapter proteins promote podosome biogenesis facilitating extracellular matrix degradation and cancer invasion

Classification models for Invasive Ductal Carcinoma Progression, based on gene expression data-trained supervised machine learning

Distinct Requirements for Adaptor Proteins NCK1 and NCK2 in Mammary Gland Development

Contact Info

Product

Resources

About