In the present study, these two compounds were evaluated further in a breast cancer (MDA-MB-231) tumour xenograft model for imaging active tissue transglutaminase in vivo.
The CGC haplotype increased the risk to breast cancer by 2.5-fold compared to others, while TGC and TTC haplotypes carried 2.5- and 5-fold lower risk of breast cancer, respectively.
For survival analyses, the results demonstrated that the minor allele homozygotes of rs13689 and haplotype TGC in CDH1 were linked with unfavorable event-free survival of breast cancer, whereas, rs4783689 of CDH1 showed the opposite effect under dominant model.
Human breast cancer cell lines (MCF7 and T47D), which express low endogenous levels of transglutaminase, were transiently transfected with the cross-linking 55 kDa active TG isoform or its precursor the 80 kDa full-length TGC.
Haplotype analysis showed that FTO TAC haplotype (rs9939609-rs1477196-rs1121980) had significant reduced breast cancer risk (OR = 0.76, 95% CI: 0.62-0.93) compared with TGC haplotype.
This manuscript reviews the literature that supports the existence of the TG2/NF-κB signaling loop, the nature of the signal transduction that activates this loop, and the phenotypic consequences stemming from the aberrant activation of this novel signaling mechanism in breast cancer.
In haplotype analysis, CCGAG haplotype in CD27 and TAA haplotype in CD70 conferred an increased risk of breast cancer (P = 5.60 × 10(-3); P = 7.75 × 10(-5), respectively), but TGC, TAC and TGA haplotypes in CD70 were associated with a decreased risk of breast cancer (P = 0.01; P = 5.2 × 10(-3); P = 2.00 × 10(-3), respectively).
The effect of TG2 expression on human breast cancer distant metastasis was investigated by analyzing a tissue microarray of primary tumors from 412 patients with their clinical data after 7 years.
We have recently uncovered that the TG2 gene (TGM2) is a target for epigenetic silencing in breast cancer, highlighting a molecular mechanism that drives reduced TG2 expression, and this aberrant molecular event may contribute to invasiveness in this tumor type.
In conclusion, we showed that p70S6K plays an important role in metastasis by regulating key proteins like cyclin D1, PDCD4, focal adhesion kinase, E-cadherin, beta-catenin, and tissue transglutaminase 2, which are essential for cell attachment, survival, invasion, and metastasis in breast cancer.
Surprisingly, the tTG-promoted growth of breast-cancer cells is dependent on its ability to activate the Src tyrosine kinase as an outcome of a complex formed between tTG and the breast-cancer marker and intermediate filament protein keratin-19.
When these three SNPs were examined as a haplotype, only the haplotype that included the G allele of rs2289046 was associated with breast cancer (odds ratio = 0.76, 95% confidence interval = 0.63-0.92 for TGC versus CAT).
A role for tissue transglutaminase (TG2) and its substrate dual leucine zipper-bearing kinase (DLK), an upstream component of the c-Jun N-terminal kinase (JNK) signaling pathway, has been previously suggested in the apoptotic response induced by calphostin C. In the current study, we directly tested this hypothesis by examining via pharmacological and RNA-interference approaches whether inhibition of expression or activity of TG2, DLK and JNK in mouse NIH 3T3 fibroblasts and human MDA-MB-231 breast cancer epithelial cells affects calphostin C-induced apoptosis.
This work indicates that the TGM2 gene is a target for epigenetic silencing in breast cancer and suggests that this aberrant molecular event is a potential marker for chemotherapeutic drug sensitivity.
We have found previously that development of the drug resistance and metastatic phenotypes in breast cancer cells is associated with increased tissue transglutaminase (TG2) expression.