Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The majority of clinical deaths in patients with triple-negative breast cancer (TNBC) are due to chemoresistance and aggressive metastases, with high prevalence in younger women of African ethnicity. Although tumorigenic drivers are numerous and varied, the drivers of metastatic transition remain largely unknown. Here, we uncovered a molecular dependence of TNBC tumors on the TRIM37 network, which enables tumor cells to resist chemotherapeutic as well as metastatic stress. TRIM37-directed histone H2A monoubiquitination enforces changes in DNA repair that rendered TP53-mutant TNBC cells resistant to chemotherapy. Chemotherapeutic drugs triggered a positive feedback loop via ATM/E2F1/STAT signaling, amplifying the TRIM37 network in chemoresistant cancer cells. High expression of TRIM37 induced transcriptomic changes characteristic of a metastatic phenotype, and inhibition of TRIM37 substantially reduced the in vivo propensity of TNBC cells. Selective delivery of TRIM37-specific antisense oligonucleotides using antifolate receptor 1-conjugated nanoparticles in combination with chemotherapy suppressed lung metastasis in spontaneous metastatic murine models. Collectively, these findings establish TRIM37 as a clinically relevant target with opportunities for therapeutic intervention. SIGNIFICANCE: TRIM37 drives aggressive TNBC biology by promoting resistance to chemotherapy and inducing a prometastatic transcriptional program; inhibition of TRIM37 increases chemotherapy efficacy and reduces metastasis risk in patients with TNBC.
 ...
PMID:Oncogenic TRIM37 Links Chemoresistance and Metastatic Fate in Triple-Negative Breast Cancer. 3285 8

Colorectal cancers (CRC) with microsatellite instability (MSI) or mismatch repair-deficiency (dMMR), but without detectable MMR germline mutations are termed Lynch-like syndrome (LLS). We assess the clinicopathologic and molecular characteristics of LLS tumors and the proportion in LLS, which remain poorly investigated in China. We enrolled 404 CRC patients with surgery in our institution from 2014 to 2018. LLS tumors were detected by a molecular stratification based on MMR protein expression, MLH1 methylation and MMR gene mutation. LLS tumors were profiled for germline mutations in 425 cancer-relevant genes. Among 42 MMR-deficient tumors, 7 (16.7%) were attributable to MLH1 methylation and 7 (16.7%) to germline mutations, leaving 28 LLS cases (66.6%). LLS tumors were diagnosed at a mean age of 60.7 years, had an almost equivalent ratio among rectum, left colon and right colon, and had high rates of lymph node metastases (50%, 4/28 N2). Most MMR gene mutations (88.2%, 15/17) in LLS tumors were variants of unknown significance (VUS). Two novel frameshift mutations were detected in ATM and ARID1A, which are emerging as candidate responsible genes for LLS. In this study, 28 (66.6%) MMRd tumors were classified as LLS, which were significantly higher than reports of western countries. LLS tumors were more likely to carry lymph node metastases. However, it's hard to differentiated LLS tumors from LS through family history, tumor location, histological type of tumors, immunohistochemistry (IHC) for MMR proteins and MSI analysis.
 ...
PMID:Molecular screening and clinicopathologic characteristics of Lynch-like syndrome in a Chinese colorectal cancer cohort. 3329 77


<< Previous 1 2 3 4 5 6