The 17q12-q21 amplicon: Her2 and topoisomerase-II alpha and their importance to the biology of solid tumours
ABSTRACT Her2 and topoisomerase-IIalpha (T2A) gene amplification are separate events, although the latter is more frequently seen in Her2 amplified (34-90%) than in Her2 non-amplified (5-10%) tumours. There is a better correlation between Her2 amplification and protein overexpression in breast cancer (BC) than in other tumour types. This marker is also considered a powerful prognostic factor in BC, with similar data emerging in other solid tumours such as bladder, ovarian, endometrial, gastro-oesophageal and non-small cell lung cancer. Her2 amplification and/or overexpression are highly predictive of response to HER2-targeted compounds such as trastuzumab and lapatinib but have been inconsistent predictors of response to cytotoxic chemotherapy. There is also evidence that these tumours are relatively resistant to anti-oestrogen therapy (tamoxifen) but not to oestrogen deprivation (e.g. with aromatase inhibitors). T2A aberrations are uncommon events in solid tumours, with an overall prevalence of approximately 10%. T2A amplification has shown inconsistent correlation with T2A protein expression in preclinical and clinical studies, mainly because non-genetic events such as proliferation rate can also affect protein expression. Expression of T2A protein has not been shown to reliably predict response to T2A inhibitors, despite the fact that this enzyme is the direct target for these compounds. In BC, T2A amplification appears to be a good predictor of response to anthracyclines, but these data are still in the process of validation. The significance of T2A deletions is currently under investigation, but contrary to what was previously thought, it may also predict benefit from treatment with T2A inhibitors. The prognostic significance of T2A aberrations is currently unknown.
- SourceAvailable from: Balázs Györffy
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- "As it was examined in the last decades, overexpression of individual genes can be associated with resistance against given agents. ABCB1 gene strongly correlates to chemoresistance (Clarke et al 1992; Kamata et al, 2008; Larbcharoensub et al, 2008; Shi et al, 2008), TOP2A is a potential gene for predicting anthracyclin resistance (Molina et al, 2005; Tanner et al, 2006; Harris et al, 2007; Mano et al, 2007). Expression of metallothioneins is linked to tamoxifen resistance (Surowiak et al, 2004), and the gene Tau is a predictor of resistance against neoadjuvant paclitaxel therapy (Rouzier et al, 2005; Andre et al, 2007). "
ABSTRACT: To date individual markers have failed to correctly predict resistance against anticancer agents in breast cancer. We used gene expression patterns attributable to chemotherapy-resistant cells to detect potential new biomarkers related to anthracycline resistance. One of the genes, PSMB7, was selected for further functional studies and clinical validation. We contrasted the expression profiles of four pairs of different human tumour cell lines and of their counterparts resistant to doxorubicin. Observed overexpression of PSMB7 in resistant cell lines was validated by immunohistochemistry. To examine its function in chemoresistance, we silenced the gene by RNA interference (RNAi) in doxorubicin-resistant MCF-7 breast cancer cells, then cell vitality was measured after doxorubicin treatment. Microarray gene expression from GEO raw microarray samples with available progression-free survival data was downloaded, and expression of PSMB7 was used for grouping samples. After doxorubicin treatment, 79.8+/-13.3% of resistant cells survived. Silencing of PSMB7 in resistant cells decreased survival to 31.8+/-6.4% (P>0.001). A similar effect was observed after paclitaxel treatment. In 1592 microarray samples, the patients with high PSMB7 expression had a significantly shorter survival than the patients with low expression (P<0.001). Our findings suggest that high PSMB7 expression is an unfavourable prognostic marker in breast cancer.British Journal of Cancer 12/2009; 102(2):361-8. DOI:10.1038/sj.bjc.6605478 · 4.82 Impact Factor
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- "It also indicates the importance of being able to refine this complex dataset down to a single credible target recognisable as significant. Given that there are other established routes to ERBB2 overexpression in breast tumours including genomic amplification [Mano et al., 2007], the clinically significant facet of the work is not the mechanism, which is not directly testable in the clinical material, but the correlation. What the field lacks is an association between the site and the proteins in ChIP from clinical material and this is universally true for research that seeks to employ ChIP to shed light on transcriptional networks in cancer. "
ABSTRACT: Chromatin immunoprecipitation (ChIP), when paired with sequencing or arrays, has become a method of choice for the unbiased identification of genomic-binding sites for transcription factors and epigenetic marks in various model systems. The data generated is often then interpreted by groups seeking to link these binding sites to the expression of adjacent or distal genes, and more broadly to the evolution of species, cell fate/differentiation or even cancer development. Against this backdrop is an ongoing debate over the relative importance DNA sequence versus chromatin structure and modification in the regulation of gene expression (Anon. 2008a Nature 454: 795; Anon. 2008b Nature 454: 711-715; Henikoff et al. 2008 Science 322: 853; Madhani et al. 2008 Science 322: 43-44). Rationally there is a synergy between the two and the goal of a biologist is to characterise both comprehensively enough to explain a cellular phenotype or a developmental process. If this is truly our goal then the critical factor in good science is an awareness of the constraints and potential of the biological models used. The reality however is often that this discussion is polarised by funding imperatives and the need to align to a transcription factor or epigenetic camp. This article will discuss the extrapolations involved in using ChIP data to draw conclusions about these themes and the discoveries that have resulted.Journal of Cellular Biochemistry 05/2009; 107(1):19-29. DOI:10.1002/jcb.22080 · 3.37 Impact Factor
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- "These areas may also contain genes that through gain or loss of function could cooperate to establish the biology of HER2 amplified tumors. The topoisomerase IIa (TOP2A) gene on 17q21 is frequently co-amplified with HER2 and may explain why HER2 overrexpressing breast cancers are particularly sensitive to treatment with topoisomerase inhibitors (Mano et al. 2006). "
ABSTRACT: The year 2007 marks exactly two decades since Human Epidermal Growth Factor Receptor-2 (HER2) was functionally implicated in the pathogenesis of human breast cancer. This finding established the HER2 oncogene hypothesis for the development of some human cancers. The subsequent two decades have brought about an explosion of information about the biology of HER2 and the HER family. An abundance of experimental evidence now solidly supports the HER2 oncogene hypothesis and etiologically links amplification of the HER2 gene locus with human cancer pathogenesis. The molecular mechanisms underlying HER2 tumorigenesis appear to be complex and a unified mechanistic model of HER2-induced transformation has not emerged. Numerous hypotheses implicating diverse transforming pathways have been proposed and are individually supported by experimental models and HER2 may indeed induce cell transformation through multiple mechanisms. Here I review the evidence supporting the oncogenic function of HER2, the mechanisms that are felt to mediate its oncogenic functions, and the evidence that links the experimental evidence with human cancer pathogenesis.Oncogene 11/2007; 26(45):6469-87. DOI:10.1038/sj.onc.1210477 · 8.56 Impact Factor