Purpose: Kruppel-like factor (KLF5) is a cell growth mediator in various epithelial cells. Higher KLF5 increases cell growth rate and leads to transformed phenotypes. Because tumor cell proliferation is tightly associated with tumor progression, and consequently, with survival of cancer patients, we wanted to examine the prognostic value of KLF5 gene expression for patients with breast cancer. Experimental Design: The gene expression levels of KLF5, ER, PR, HER2, and MKI67 were quantified in the tumor tissues of 90 patients with breast cancer and correlated with disease-free survival and overall survival of the patients. The correlations of gene expression between KLF5 and ER, PR, HER2, and MKI67 were analyzed. In addition, KLF5 expression was also compared with clinical data and age of patients. Results: Statistically significant correlations were found between gene expression of KLF5 and both disease-free survival (univariate analysis) and overall survival (univariate and multivariate analysis). Patients with higher KLF5 expression had shorter disease-free survival and overall survival time, whereas patients with lower KLF5 expression had better survival. Moreover, KLF5 was also found to be positively correlated with HER2 and MKI67, and negatively correlated with age of the patients at diagnosis. Conclusion: The gene expression of KLF5 is directly correlated with cell proliferation in vivo and is a prognostic factor for patients with breast cancer. Patients with higher KLF5 expression have shorter disease-free survival and overall survival than patients with lower KLF5 expression. In addition, KLF5 has higher expression in patients ages V50 years old than in patients >50 years old.Kruppel-like factor 5 (KLF5), also called intestinal-enriched KLF5, is a DNA-binding transcriptional regulator, and contains three independent peptide modules of the C 2 H 2 zinc finger type (1). KLF5 gene expression is well-regulated in embryos, with a higher level of expression towards the later stage of fetal development. It is widely expressed in human tissues including colon, small intestine, prostate, pancreas, kidney, skeletal muscle, lung, and breast (2 -4). In the intestinal tract, KLF5 expression is concentrated at the base of the crypt epithelium in which active cell division occurs (5).KLF5 has been reported to have growth-promoting effects in cultured cells based on a number of studies. Constitutive expression of KLF5 results in an increased rate of proliferation, and eventually, in a transformed phenotype, as characterized by anchorage-independent growth (6, 7). This regulatory function of KLF5 on cell proliferation might be through the stimulation of cyclin D1 (8), cyclin B1, and Cdc2 gene expression (9), or by mediating the inhibitory effect of retinoids on cell proliferation (7). KLF5 was also shown to regulate the pro-proliferative and transforming activities of oncogenic H-ras. In oncogenic H-rastransformed NIH3T3 cells, an elevated level of KLF5 transcript was shown. The accelerated proliferation and the ...
Most patients with epithelial ovarian cancer (EOC) are diagnosed at advanced stage and have a poor prognosis. However, a small proportion of these patients will survive, whereas others will die very quickly. Clinicopathological factors do not allow precise identification of these subgroups. Thus, we have validated a molecular subclassification as new prognostic factor in EOC. One hundred and ninety-four patients with Stage II-IV EOC were characterized by whole-genome expression profiling of tumor tissues and were classified using a published 112 gene set, derived from an International Federation of Gynecology and Obstetrics (FIGO) stage-directed supervised classification approach. The 194 tumor samples were classified into two subclasses comprising 95 (Subclass 1) and 99 (Subclass 2) tumors. All nine FIGO II tumors were grouped in Subclass 1 (P = 0.001). Subclass 2 (54% % of advancedstage tumors) was significantly correlated with peritoneal carcinomatosis and non-optimal debulking. Patients with Subclass 2 tumors had a worse overall survival for both serous and non-serous histological subtypes, as revealed by univariate analysis (hazard ratios [HR] of 3.17 and 17.11, respectively; P 0.001) and in models corrected for relevant clinicopathologic parameters (HR 2.87 and 12.42, respectively; P 0.023). Significance analysis of microarrays revealed 2082 genes that were differentially expressed in advanced-grade serous tumors of both subclasses and the focal adhesion pathway as the most deregulated pathway. In the present validation study, we have shown that, in advanced-stage serous ovarian cancer, two approximately equally large molecular subtypes exist, independent of classical clinocopathological parameters and presenting with highly different whole-genome expression profiles and a markedly different overall survival. Similar results were obtained in a small cohort of patients with non-serous tumors. (Cancer Sci 2012; 103: 1334-1341
L1CAM expression contributes to the invasive and metastatic phenotype of serous ovarian carcinoma. L1CAM expression and shedding in the tumor microenvironment could contribute to enhanced invasion and tumor progression through increased IL-1β production and NF-κB activation.
Purpose: We aimed to determine the clinical role of the p53 family members p53 and p73 in the responsiveness to platinum-based chemotherapy and survival in ovarian cancer, considering their cross-talk and the p53 polymorphism at codon 72. Experimental Design: A detailed analysis of p53 and p73 in a series of122 ovarian cancers was done.We used a functional yeast-based assay to determine the p53 mutational status. Red yeast colonies, indicating mutant p53, were subsequently sequenced to determine the specific p53 alteration. p53 mutations were divided into two groups according to their previous characterization in the literature: those that efficiently inhibit transcriptionally activeTAp73 function and those that do not. A p53 polymorphism at codon 72 was determined in corresponding normal tissue or blood of ovarian cancer patients. Isoform-specific p73 expression analysis using real-time reverse transcription-PCR has previously been done in the majority of ovarian cancers included in this study. In a retrospective chart review, responsiveness to chemotherapy was assessed, and survival data with long follow-up times were collected. Results: Eighty of 122 (65.6%) of ovarian cancers harbored p53 mutations. p53 mutational status was an important determinant of responsiveness to platinum-based chemotherapy in all patients with a residual tumor of <2 cm in diameter after initial surgery (wild-type versus mutant, P = 0.029). In addition, p53 mutational status was a strong prognosticator for recurrence-free and overall survival (P < 0.0001and P = 0.003, respectively) in univariate analyses. High expression levels of dominant-negative p73 isoforms (DNp73 and DNVp73) significantly correlated with chemotherapeutic failure (P = 0.048) and with worse recurrence-free and overall survival in patients with p53 mutant cancers (P = 0.048 and P = 0.005, respectively). Eight p53 mutations, present in 19 cases, were found that efficiently inhibit TAp73 (i.e., 175H, 220C, 245S, 245D, 248W, 248Q, 266E, and 273H). Patients with p53 mutations that efficiently inhibit TAp73 function had a significantly shorter overall survival than patients with p53 mutations of unknown effect on TAp73 (P = 0.044). The p53 polymorphism at codon 72 had no influence on responsiveness to chemotherapy or survival. Conclusion: We provide the first clinical evidence that dominant-negative p73 isoforms contribute to drug resistance in vivo, underscoring the importance of a p53-p73 cross-talk. NH 2 -terminally truncated p73 isoforms were of significant clinical effect by providing an additional unfavorable factor for response to platinum-based chemotherapy and survival in p53 mutant ovarian cancers.
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