Matched primary and metastasis tissues were evaluated for intragenic mutations in KRAS, CDKN2A, and TP53 and immunolabeled for CDKN2A, TP53, and SMAD4 protein products.
To elucidate how mutant p53 GOF drives metastasis, we developed a traceable somatic osteosarcoma mouse model that is initiated with either a single <i>p53</i> mutation (p53R172H) or <i>p53</i> loss in osteoblasts.
The combined results reveal PGC-1α as a novel "gain-of-function" partner of mutant p53 and indicate that the codon 72 polymorphism influences the impact of mutant p53 on metabolism and metastasis.
TP53 is associated with human cancer by mutations that lead to a loss of wild-type p53 function as well as mutations that confer alternate oncogenic functions that enable them to promote invasion, metastasis, proliferation, and cell survival.
Polymorphisms of HER2Ile655Val and cyclin D1 (CCND1) G870A are not associated with breast cancer risk but polymorphic allele of HER2 is associated with nodal metastases.
Tumors with TP53 mutations or with TP53 and TERT promoter mutations were almost always classified as high risk, and the patients developed metastases and/or died of disease.
In addition, we correlated the findings with other relevant molecular markers including the metastasis associated nm23-H1 gene and loss of heterozygosity (LOH) using multiple polymorphic markers for chromosome 17p and sequencing the entire open reading frame (ORF) of the p53 gene.
Remarkably, we observed that the mutational status of the TP53 gene is associated significantly with the degree of genetic differences between primary HNSCCs and corresponding metastases.
Furthermore, the presence of p53 mutations in the surgical margins may not increase the risk of local-regional recurrence, but probably increases the risk of developing distant metastases or second primary tumors.
Herein we describe construction of a nanosensor for matrix metalloproteinase 9 (MMP9), which is associated with tumor progression and metastasis, for detection of colorectal cancer in a mouse model.
Three types of membrane type-matrix metalloproteinases (MT-MMPs) have been identified as activators of pro-MMP2 (gelatinase A/72-kilodalton Type IV collagenase), which is believed to be crucial for tumor invasion and metastasis.
We identified a novel association between a TP53 rare variant and metastasis at diagnosis of osteosarcoma (rs1800372, odds ratio = 4.27, 95% confidence interval = 1.2 to 15.5, P = .026).
Subsequently, a non-Kras mutation-induced premalignancy mouse model was developed; in this model, APC haploinsufficiency coupled with p53 deletion resulted in the development of a distinct type of pancreatic premalignant precursors, mucinous cystic neoplasms (MCNs), exhibiting pathomechanisms identical to those observed in human MCNs, including accumulation of cystic fluid secreted by neoplastic and ovarian-like stromal cells, with 100% penetrance and the presence of hepatic and gastric metastases in >30% of the mice.
In addition, the presence of one G allele in SNPs rs1360485 or rs2249825 was associated with a higher risk of progressing to T2 tumor and distant metastasis amongst HER2-enriched and triple-negative breast cancer (TNBC) tumors compared with luminal A and luminal B tumors.
The ERBB2 mutation status was determined by next generation sequencing and/or pyrosequencing in n = 106 ILBCs, including n = 86 primary or locally recurrent tumors and n = 20 metastases from visceral organs, soft tissue, or skin.
Understanding the mechanisms by which p53 loss and mutation promote tumor metastasis is crucial to understanding the biology of tumor progression and how to appropriately apply targeted therapies.