Division of Medical Oncology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON M4N 3M5, Canada. New England Journal of Medicine
(Impact Factor: 55.87).
09/2011; 365(11):1025-32. DOI: 10.1056/NEJMcp1101540
Available from: Sofia Chrisafi
- "Despite recent advances in molecular biology and therapeutics, breast cancer remains a highly lethal malignancy worldwide . Early breast cancer represents a heterogeneous disease entity, that can be further categorized by the use of simple immunohistochemical (IHC) molecular markers, including the estrogen receptor (ER), the progesterone receptor (PgR), the epidermal growth factor receptor (EGFR), the c-erbB2 (HER2/neu) receptor, the mitotic index Ki67 and the cytokeratines 5/6 . "
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ABSTRACT: We sought to determine the level of protein expression of the critical components of the insulin-like growth factor receptor (IGFR) pathway and to evaluate their prognostic significance across the different early breast cancer subtypes.
Archival tumor tissue from 1,021 women with early, node positive breast cancer, who were prospectively evaluated within two randomized clinical trials, was used to construct tissue microarrays that were stained for hormone receptors (HR), Ki67, HER2, epidermal growth factor receptor (EGFR) and cytokeratins 5/6, to classify tumors into five immunophenotypical subgroups. Immunohistochemical (IHC) expression of IGF1R-alpha and beta subunits, IGF2R and IGF-binding protein 2 (IGFBP2) was assessed using the immunoreactive score (IRS). Repeated internal cross-validation was performed to examine the statistical validity of the cut off points for all biomarkers.
After a median follow-up time of 105.4 months, overall 370 women (36.2%) had relapsed and 270 (26.4%) had died. Tumors expressing IGF1R-alpha above the median IRS were significantly more frequently HR positive (luminal A+B+HER2), as compared to HER2-enriched and triple negative ones (p<0.001 for both comparisons). IGF2R was overexpressed significantly more frequently in HR negative tumors (p = 0.001) and had an inverse correlation with all other biomarkers. Patients with luminal A and B tumors with high IGF1R-alpha and negative EGFR expression (N = 190) had significantly higher 4-year survival rates, as compared to the rest (log-rank p = 0.046), as did patients with luminal A and B tumors with high IGF1R-alpha and low IGF2R expression, as compared to the rest (N = 91), (log-rank p = 0.035). After adjustment for significant variables, patients in the latter group had a relative 45% reduction in the risk of death, as compared to the rest (p = 0.035).
Aberrant expression of components of the IGF1R pathway is associated with better clinical outcomes in women with luminal A and B, node positive, early breast cancer.
Available from: link.springer.com
- "Breast cancer is one of the leading causes of cancer death worldwide , and the most common cancer among women . Expression of the cell surface protein biomarkers estrogen receptor (ER) and progesterone receptor (PR) have long been associated with a more favorable prognosis, while the presence of an amplification in the HER2/neu gene confers sensitivity to the targeted chemotherapeutic agent herceptin [19,20]. "
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ABSTRACT: Discovering robust prognostic gene signatures as biomarkers using genomics data can be challenging. We have developed a simple but efficient method for discovering prognostic biomarkers in cancer gene expression data sets using modules derived from a highly reliable gene functional interaction network. When applied to breast cancer, we discover a novel 31-gene signature associated with patient survival. The signature replicates across five independent gene expression studies, and outperforms 48 published gene signatures. When applied to ovarian cancer, the algorithm identifies a 75-gene signature associated with patient survival. A Cytoscape plugin implementation of the signature discovery method is available at http://wiki.reactome.org/index.php/Reactome_FI_Cytoscape_Plugin.
Available from: PubMed Central
- "Breast cancer is the most common cancer in women worldwide and the leading cause of death among women with cancer . It has been estimated that 230, 480 women would be diagnosed with and 39, 520 women would die of cancer of the breast in 2011. "
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ABSTRACT: Claudin-6 is a candidate tumor suppressor gene in breast cancer, and has been shown to be regulated by DNA methylation and histone modification in breast cancer lines. However, the expression of claudin-6 in breast invasive ductal carcinomas and correlation with clinical behavior or expression of other markers is unclear. We considered that the expression pattern of claudin-6 might be related to the expression of DNA methylation associated proteins (methyl-CpG binding protein 2 (MeCP2) and DNA methyltransferase 1 (DNMT1)) and histone modification associated proteins (histone deacetylase 1 (HDAC1), acetyl-histone H3 (H3Ac) and acetyl- histone H4 (H4Ac)).
We have investigated the expression of claudin-6, MeCP2, HDAC1, H3Ac and H4Ac in 100 breast invasive ductal carcinoma tissues and 22 mammary gland fibroadenoma tissues using immunohistochemistry.
Claudin-6 protein expression was reduced in breast invasive ductal carcinomas (P < 0.001). In contrast, expression of MeCP2 (P < 0.001), DNMT1 (P = 0.001), HDAC1 (P < 0.001) and H3Ac (P = 0.004) expressions was increased. Claudin-6 expression was inversely correlated with lymph node metastasis (P = 0.021). Increased expression of HDAC1 was correlated with histological grade (P < 0.001), age (P = 0.004), clinical stage (P = 0.007) and lymph node metastasis (P = 0.001). H3Ac expression was associated with tumor size (P = 0.044) and clinical stage of cancers (P = 0.034). MeCP2, DNMT1 and H4Ac expression levels did not correlate with any of the tested clinicopathological parameters (P > 0.05). We identified a positive correlation between MeCP2 protein expression and H3Ac and H4Ac protein expression.
Our results show that claudin-6 protein is significantly down-regulated in breast invasive ductal carcinomas and is an important correlate with lymphatic metastasis, but claudin-6 down-regulation was not correlated with upregulation of the methylation associated proteins (MeCP2, DNMT1) or histone modification associated proteins (HDAC1, H3Ac, H4Ac). Interestingly, the expression of MeCP2 was positively correlated with the expression of H3Ac and H3Ac protein expression was positively correlated with the expression of H4Ac in breast invasive ductal carcinoma VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/4549669866581452.
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