Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Breast cancer stromal compartment, may influence responsiveness to chemotherapy. Our aim was to detect a stromal cell signature (using a direct approach of microdissected stromal cells) associated with response to neoadjuvant chemotherapy (neoCT) in locally advanced breast cancer (LABC). The tumor samples were collected from 44 patients with LABC (29 estrogen receptor (ER) positive and 15 ER negative) before the start of any treatment. Neoadjuvant chemotherapy consisted of doxorubicin and cyclophosphamide, followed by paclitaxel. Response was defined as downstaging to maximum ypT1a-b/ypN0. The stromal cells, mainly composed of fibroblast and immune cells, were microdissected from fresh frozen tumor samples and gene expression profile was determined using Agilent SurePrint G3 Human Gene Expression microarrays. Expression levels were compared using MeV (MultiExperiment Viewer) software, applying SAM (significance analysis of microarrays). To classify samples according to tumor response, the order of median based on confidence statements (MedOr) was used, and to identify gene sets correlated with the phenotype downstaging, gene set enrichment analysis (GSEA). Nine patients presented disease downstaging. Eleven sequences (FDR 17) were differentially expressed, all of which (except H2AFJ) more expressed in responsive tumors, including PTCHD1 and genes involved in abnormal cytotoxic T cell physiology, TOX, LY75, and SH2D1A. The following four pairs of markers could correctly classify all tumor samples according to response: PTCHD1/PDXDC2P, LOC100506731/NEURL4, SH2D1A/ENST00000478672, and TOX/H2AFJ. Gene sets correlated with tumor downstaging (FDR < 0.01) were mainly involved in immune response or lymphocyte activation, including CD47, LCK, NCK1, CD24, CD3E, ZAP70, FOXP3, and CD74, among others. In locally advanced breast cancer, stromal cells may present specific features of immune response that may be associated with chemotherapy response.
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PMID:Stromal Cell Signature Associated with Response to Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer. 3181 55

The centrosome is the microtubule organizing center of human cells and facilitates a myriad of cellular functions including organization of the mitotic spindle to ensure faithful chromosome segregation during mitosis, cell polarization and migration, and primary cilia formation. A numerical increase in centrosomes, or centrosome amplification (CA), is common in cancer and correlates with more aggressive clinical features and worse patient outcomes. However, the causes of CA in human cancer are unclear. Many previous studies have identified mechanisms of CA in cellulo, such as overexpression of PLK4, but it is unclear how often these are the primary mechanism in human disease. To identify a primary cause of CA, we analyzed The Cancer Genome Atlas (TCGA) genomic and transcriptomic data for genes encoding the 367 proteins that localize to the centrosome (the "centrosome-ome"). We identified the following candidates for primary causes of CA: gain-of-function alterations of CEP19, CEP72, CTNNB1, PTK2, NDRG1, SPATC1, TBCCD1; and loss-of-function alterations of CEP76, MCPH1, NEURL4, and NPM1. In cellulo analysis of these candidates revealed that loss of MCPH1/microcephalin caused the most robust increase in centriole number. MCPH1 deep gene deletions are seen in 5-15% of human cancers, depending on the anatomic site of the tumor. Mechanistic experiments demonstrated that loss of MCPH1 caused a CDK2-dependent increase in STIL levels at the centrosome to drive CA. We conclude that loss of MCPH1 is common in human cancer and is likely to be a cause of CA.
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PMID:Analysis of the "centrosome-ome" identifies MCPH1 deletion as a cause of centrosome amplification in human cancer. 3268 Oct 70