New Biomarkers to Predict the Evolution ofIn SituBreast Cancers (original) (raw)
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New Biomarkers to Predict the Evolution ofIn SituBreast Cancers
BioMed Research International, 2014
Background.Genomic studies have shown that gene expression profiles are similar inin situ(CIS) and invasive breast cancers, suggesting that several biofunctional modifications of the transformation process occur before or during the development of CIS lesion.Methods.We investigated 3 biomarkers in 44 patients with CIS: TG2 (transglutaminase 2), HJURP (Holliday junction recognition protein), and HIF-1α (hypoxia inducible factor-1 alpha).Results.TG2 was more highly expressed than the other two markers and significantly more so in stromal than in tumor cells. HIF-1α evaluation showed a higher expression in both tumor and stromal cells in patients with relapsed G3 tumors, indicating a potential role of this marker in CIS evolution. A greater than sevenfold higher risk of relapse(P=0.050)was observed in patients highly expressing HJURP in stroma and a tenfold higher recurrence risk(P=0.026)was seen in those with a higher stromal HIF-1α expression. An important increase in risk accuracy (...
Cancer Research, 2008
Differential regulation as well as target gene specificity of the two hypoxia-inducible factor (HIF)-A subunits HIF-1A and HIF-2A in various tumors and cell lines have been suggested. In breast cancer, the prognostic significance of HIF-1A is not clear-cut and that of HIF-2A is largely unknown. Using IHC analyses of HIF-1A, HIF-2A, and vascular endothelial growth factor (VEGF) expression in a tissue microarray of invasive breast cancer specimens from 512 patients, we investigated the expression patterns of the 2 HIF-A subunits in relation to established clinicopathologic variables, VEGF expression, and survival. HIF-1A and HIF-2A protein levels and their effect on survival were additionally analyzed in a second cohort of 179 patients. To evaluate the individual role of each subunit in the hypoxic response and induction of VEGF, HIF-A protein and HIF-A and VEGF mRNA levels were further studied in cultured breast cancer cells after hypoxic induction and/or knockdown of HIF-A subunits by siRNA by Western blot and Quantitative Real-Time PCR techniques. We showed that although HIF-1A and HIF-2A protein levels in breast cancer specimens were not interrelated, high levels of both HIF-1A and HIF-2A associated to high VEGF expression. HIF-2A expression was an independent prognostic factor associated to reduced recurrence-free and breast cancer-specific survival, whereas HIF-1A did not exhibit these correlations. In cultured cells, acute hypoxia induced both HIF-proteins. At prolonged hypoxia, HIF-2A remained accumulated, whereas HIF-1A protein levels decreased, in agreement with the oxygen level and timedependent induction of HIFs recently reported in neuroblastoma. [Cancer Res 2008;68(22):9212-20]
Breast Cancer Res, 2004
Background The transcription factor hypoxia-inducible factor-1 (HIF-1) is a key regulator of the cellular response to hypoxia. Previous studies showed that concentrations of its subunit HIF-1α, as a surrogate for HIF-1 activity, are increased during breast carcinogenesis and can independently predict prognosis in breast cancer. During carcinogenesis, the cell cycle is progressively deregulated, and proliferation rate is a strong prognostic factor in breast cancer. In this study we undertook a detailed evaluation of the relationships between HIF-1α and cell cycle-associated proteins. Methods In a representative estrogen receptor (ER) group of 150 breast cancers, the expression of HIF-1α, vascular endothelial growth factor, the ER, HER-2/neu, Ki-67, cyclin A, cyclin D 1 , p21, p53, and Bcl-2 was investigated by immunohistochemistry. Results High concentrations (5% or more) of HIF-1α were associated with increased proliferation as shown by positive correlations with Ki-67 (P < 0.001) and the late S-G2-phase protein cyclin A (P < 0.001), but not with the G1-phase protein cyclin D 1. High HIF-1α concentrations were also strongly associated with p53 positivity (P < 0.001) and loss of Bcl-2 expression (P = 0.013). No association was found between p21 and HIF-1α (P = 0.105) in the whole group of patients. However, the subgroup of ER-positive cancers was characterized by a strong positive association between HIF-1α and p21 (P = 0.023), and HIF-1α lacked any relation with proliferation. Conclusion HIF-1α overexpression is associated with increased proliferation, which might explain the adverse prognostic impact of increased concentrations of HIF-1α in invasive breast cancer. In ER-positive tumors, HIF-1α is associated with p21 but not against proliferation. This shows the importance of further functional analysis to unravel the role of HIF-1 in late cell cycle progression, and the link between HIF-1, p21, and ER.
Oncology Letters, 2013
The understanding of the molecular mechanisms that underlie all stages of tumor progression in breast cancer (BC) represents an important goal in the biomedical research of this disease, particularly for the identification of more specific targeted therapies. In this context, BC preinvasive and precursor lesions represent a major dilemma. These lesions are well characterized under the phenotypic and genotypic profile, but it is not clear if they represent obligatory passages of a multistep process determining breast cancer evolution. In fact, the numerous cytogenetic and molecular alterations identified are not always representative of the progression into invasive phenotypes.
Molecular phenotypes of matched in situ and invasive components of breast carcinomas
Human Pathology, 2011
The current system of pathologic classification of human breast cancers does not take into account the biologic determinants of prognosis, nor is there a consensus regarding the progression from in situ to invasive carcinoma. The present study compared the molecular phenotypes of in situ and invasive components of breast cancer in the same sample. We built a series of 189 in situ and invasive carcinomas using tissue microarrays and classified them according to their immunoprofiles regarding estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, epidermal growth factor receptor, cytokeratin 5, P-cadherin, and the antigen Ki-67 into luminal A and B, human epidermal growth factor receptor 2 overexpressing, and basal-like carcinomas. We also correlated the subgroups of carcinomas with some of the classical prognostic factors such as histologic grade, tumor size, and lymph node metastasis, as well as with the age of the patient at diagnosis. The overall concordance on the molecular phenotypes between in situ and invasive components was 94%. For the in situ component, 63% of the cases were luminal A; 15%, luminal B; 12%, human epidermal growth factor receptor 2 overexpressing; and 7%, basal-like. Regarding the invasive component, 61% of the cases were luminal A; 16%, luminal B; 12%, human epidermal growth factor receptor 2 overexpressing; and 8%, basal-like. The present study allowed the identification of different immunoprofiles of in situ and invasive breast carcinomas using a specific panel of biomarkers and showed that in most cases, there is a concordance between in situ and invasive component profiles, supporting the theory of parallel disease in breast tumorigenesis.
Differential regulation as well as target gene specificity of the two hypoxia-inducible factor (HIF)-A subunits HIF-1A and HIF-2A in various tumors and cell lines have been suggested. In breast cancer, the prognostic significance of HIF-1A is not clear-cut and that of HIF-2A is largely unknown.Using IHC analyses of HIF-1A, HIF-2A, and vascular endothelial growth factor (VEGF) expression in a tissue microarray of invasive breast cancer specimens from 512 patients, we investigated the expression patterns of the 2 HIF-A subunits in relation to established clinicopathologic variables, VEGF expression, and survival.HIF-1 A and HIF-2A protein levels and their effect on survival were additionally analyzed in a second cohort of 179 patients.To evaluate the individual role of each subunit in the hypoxic response and induction of VEGF, HIF-A protein and HIF-A and VEGF mRNA levels were further studied in cultured breast cancer cells after hypoxic induction and/or knockdown of HIF-A subunits by...
A genomic ruler to assess oncogenic transition between breast tumor and stroma
PloS one, 2018
Cancers induce gene expression alterations in stroma surrounding tumors that supports cancer progression. However, it is actually not at all known the extent of altered stromal gene expression enacted by tumors nor the extent to which altered stromal gene expression penetrates the stromal tissue. Presently, post-surgical "tumor-free" stromal tissue is determined to be cancer-free based on solely on morphological normality-a criteria that has not changed in more than 100 years despite the existence of sophisticated gene expression data to the contrary. We therefore investigated the extent to which breast tumors alter stromal gene expression in three dimensions in women undergoing mastectomy with the intent of providing a genomic determination for development of future risk of recurrence criteria, and to inform the need for adjuvant full-breast irradiation. Genome-wide gene expression changes were determined in histopathologically normal breast tissue in 33 women undergoing ...
Supplemental Data Regulation of In Situ to Invasive Breast Carcinoma Transition
2000
Differentially expressed tags (P < 0.05) between ITGB6+ and MUC1+ SAGE libraries from MCFDCIS xenografts were generated by Poisson analysis (available at http://genome.dfci.harvard.edu/sager/) . Normalized tag counts per 50,000 from these two libraries were combined with those from human breast epithelial and myoepithelial libraries (N-EPIand D-MYOEP-7). Tags were further filtered to have a maximum count from all libraries above 10 per 50,000 and to have a >1.5 fold difference between ITGB6 and MUC1 libraries. Filtered data were log transformed and clustered (hierarchical, complete linkage) using the Cluster and TreeView software . Color settings were adjusted to set tag count 4 per 50,000 as black. Tag counts below 4 were green and above 4 were red. Gene ontology enrichment scores for the SAGE libraries were calculated as -log(p-value) by comparing the significantly highly expressed genes in each cell type (ITGB6+ and MUC1+, or Myoep and Epi) analyzed to the background (all genes in the ITGB6+/MUC1+ libraries, or for human breast libraries, all genes with tag count >=10 per 100K in at least one library) with one-sided Fisher test. Genes were selected based on the following criteria: (1) statistically significant (p<0.05) difference between ITGB6+ and MUC1+ libraries; (2) statistically significant (p<0.05) difference between human MYOEP and EPI groups based on t-test or Wilcox test (for genes high in ITGB6+ and MYOEP or MUC1+ and EPI), or ratio of DMYOEP/NMYOEP > 10-fold (for genes high in ITGB6+ and DMYOEP);