Overexpression of TP73 variants in tumor tissues indicates that they may be involved in colon and breast carcinogenesis. The association between upregulation of DeltaTAp73 isoforms and poor prognosis features, specifically advanced tumor stage, suggests that they may be of practical clinical prognostic value. Interestingly, the in vivo associations identified here may indicate a functional network involving p73 variants, p53, and E2F-1.

ZEB1 and SNAIL repress CDH1 and induce epithelial-mesenchymal transition (EMT). However, SNAIL and ZEB1 also activate or regulate other target genes in different ways. For instance, vitamin D receptor (VDR), which activates CDH1 expression upon ligand binding, is repressed by SNAIL but induced by ZEB1. We examined whether the biological activity of SNAIL and ZEB1 in colon cancer is regulated by interacting cofactors. The mRNA expression levels of SNAIL and ZEB1, and of transcriptional regulators p300 and CtBP, were measured by RT-PCR in tumor and normal tissue from 101 colon carcinoma patients. Overexpression of SNAIL was associated with down-regulation of CDH1 and VDR (p 5 0.004 and p < 0.001). CDH1 correlated with VDR (r 5 0.49; p < 0.001). ZEB1 expression also correlated with VDR (r 5 0.23; p 5 0.019). However, when CtBP was strongly expressed, ZEB1 was inversely correlated with CDH1 (r 5 20.39; p 5 0.053). Furthermore, when there were elevated p300 expression levels, the correlation between expression of ZEB1 and VDR was stronger (r 5 0.38; p 5 0.070). Association between SNAIL expression and down-regulation of CDH1 and VDR was lost in tumors in which p300 and CtBP were strongly expressed. These results indicate that the levels of expression of CtBP and p300 are critical for the action of SNAIL and ZEB1, which have a pivotal role in EMT, and show the importance of CtBP and p300 for tumor progression. ' 2006 Wiley-Liss, Inc.Key words: human colorectal cancer; gene expression; p300; CtBP; epithelial-mesenchymal transition genes A large number of biological processes involve regulation of gene expression by transcriptional repression.1 ZEB1 and ZEB2 are transcriptional repressors that contain zinc-fingers motifs in their DNA binding domain, and both recognize the same E-boxes in their target genes.2,3 Despite the high homology and the identical overall gene structure of ZEB1 and ZEB2, there are differences in their pattern of expression, the organization of their repressor domains and their specificity.3 ZEB1 and ZEB2 repress a large number of regulators involved in differentiation and developmental events.2,4-12 One such regulator, E-cadherin (encode by CDH1 gene), is located in adherent junctions and contributes to the maintenance of the adhesive and polarized phenotype of epithelial cells.13 When E-cadherin is down-regulated, the epithelial cells acquire a fibroblastoid morphotype accompanied by invasion and migratory properties, which are associated with the epithelialmesenchymal transition (EMT). [14][15][16] This transition also occurs after expression of SNAIL, another transcriptional repressor with zinc-finger motifs that represses transcription of CDH1 even more efficiently than ZEB1 or ZEB2. 17,18 Moreover, ZEB1 expression is induced by SNAIL and persists after SNAIL is down-regulated in tumor cell lines. 18Vitamin D (1a,25-dehydroxyvitamin D3) induces the expression of CDH1 in cells expressing vitamin D receptors (VDRs). 19 We have recently shown that SNAIL also represses VDR expression in tumor cel...

This study compared the effects of two supervised concurrent training interventions in breast cancer survivors with cancer-related fatigue at baseline. Twenty-three female breast cancer survivors (50±8 years) were randomized to a high- (n=13) or a moderate-intensity (n=10) training program. Both interventions lasted 16 weeks and included the same resistance exercises, but the aerobic component was supervised and more intense in the former (i.e., rating of perceived exertion of 7–8 vs. 6 on a 1–10 scale for the high and moderate-intensity intervention, respectively). The primary endpoint was fatigue perception. Endpoints were assessed at baseline and after 16 weeks. The p-value for statistical significance was set at 0.004 after Bonferroni correction for multiple comparisons. The high-intensity training program increased lower-limb muscle strength significantly (p=0.002) and tended to improve fatigue perception (p=0.006), waist circumference (p=0.013), neutrophil-to-lymphocyte ratio (p=0.028) and some quality of life items (p=0.011). Although the moderate-intensity training program did not provide such benefits in general (i.e., higher p-values for pre vs post-intervention comparisons), no significant differences were found between interventions (all p>0.004). Further research is needed to elucidate if the benefits provided by high-intensity concurrent training are superior to those elicited by moderate-intensity training in breast cancer survivors.

PurposeTo determine the feasibility of mRNAs (C-MYC, BCL-XL, BCL-6, NF-κβ, PTEN and AKT) in exosomes of plasma as a liquid biopsy method for monitoring and prognostic evolution in B-cell lymphomas.Patients and MethodsExosomes were isolated from 98 patients with B-cell Lymphoma and 68 healthy controls. mRNAs were analyzed by quantitative PCR. An additional 31 post-treatment samples were also studied.ResultsIn the general and follicular lymphoma series, the presence of AKT mRNA was associated with poor response to rituximab-based treatment. Patients with first relapse or disease progression showed a lower percentage of PTEN and BCL-XL mRNA. The presence of BCL-6 mRNA was associated with a high death rate. The absence of PTEN mRNA in the general series, and presence of C-MYC mRNA in follicular lymphomas, were associated with short progression-free survival. BCL-6 and C-MYC mRNA were independent prognostic variables of overall survival. C-MYC mRNA may provide prognostic information with respect to overall survival. BCL-XL mRNA and increase of BCL-6 mRNA in post-treatment samples could serve as molecular monitoring markers.ConclusionsThis is the first large study to evaluate the prognostic and predictive values of pretreatment tumor-associated mRNA in exosomes. BCL-6 and C-MYC mRNA positivity in pretreatment samples were predictors of worse PFS compared to patients with mRNA negativity. C-MYC mRNA positivity was also a statistically significant predictor of inability to obtain complete response with first-line therapy.

GADD45 is a growth arrest-associated gene that is induced in response to DNA damage. This gene is a target for coordinate regulation by both ZBRK1 and BRCA1. A sequence within intron 3 of GADD45 supports specific assembly of the ZBRK1/BRCA1 complex. In this study, the relationships between GADD45, ZBRK1, and BRCA1 expression were investigated in colon carcinomas. mRNA expression of these three genes was analysed in 116 colon carcinomas by real-time reverse transcriptase polymerase chain reaction (RT-PCR). Genetic and epigenetic changes that could alter expression of these genes were studied. Possible relationships between expression levels of GADD45, ZBRK1, and BRCA1, and a series of clinicopathological parameters classically associated with poor prognosis, were also examined. ZBRK1 showed a tendency towards underexpression, while GADD45 and BRCA1 were generally overexpressed. A direct relationship between these three genes was observed, with the exception of BRCA1 expression levels, similar to normal tissues, which showed a tendency to be associated with low levels of GADD45 mRNA. Concomitantly altered expression of ZBRK1 and BRCA1 was associated with GADD45 mRNA expression. Promoter hypermethylation was not observed in GADD45 or BRCA1, and no mutations in GADD45 or ZBRK1 were found in regions involved in the interaction between the GADD45 gene and the ZBRK1 and BRCA1 proteins. No clinicopathological parameter was correlated with altered GADD45 or ZBRK1 expression but there was a statistically significant relationship between BRCA1 levels and the sex of patients. In conclusion, these results suggest that this pathway, involved in the response to DNA damage, is deregulated in colon carcinomas, and concomitantly altered expression of ZBRK1 and BRCA1 has an additive effect on GADD45 regulation. This is the first study in human carcinomas to analyse the relationships between expression of GADD45, ZBRK1, and BRCA1 mRNA.