Simultaneous Amplification of HER-2 (ERBB2) and Topoisomerase II&amp;#945; (TOP2A) Genes - Molecular Basis for Combination Chemotherapy in Cancer

Järvinen, Tero A.H.; Liu, Edison T.

doi:10.2174/156800906778742497

Cited by 56 publications

(56 citation statements)

References 171 publications

(394 reference statements)

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“…a number of studies discuss the potential role of ToP2a as a predictor of response to chemotherapy (13,14,20,24,25). although limited to a small patient group, we found stronger expression of ToP2a and Her-2 in the tumor cells of chemotherapy-naïve patients than in patients previously treated with platinum.…”

Section: Discussionmentioning

confidence: 46%

“…TOP2A amplification was correlated with HER-2 activity in the tumor epithelial cells. it is known that ToP2a appears to be a sensitive marker in ovca, and its activity is commonly associated with Her2 expression (13,14,23).…”

Section: Discussionmentioning

confidence: 99%

“…The Her-2 proto-oncogene is essential for tumor growth and proliferation, with a wide range of amplification in solid tumors (14)(15)(16). different ligands can bind through its extracellular segments, and can mediate intracellular signal transduction through tyrosine kinase activity.…”

Section: Introductionmentioning

confidence: 99%

“…Recent trials suggest that amplification (and/or deletion) of TOP2A may lead to sensitivity or resistance to clinically used ToP2a inhibitors (14). nevertheless, data regarding the expression of ToP2a and Her-2 in ovca are limited.…”

Section: Introductionmentioning

confidence: 99%

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Tumor- and stromal cell-specific expression of topoisomerase IIα and HER-2/neu in primary and recurrent ovarian cancer: Results of a prospective study

Chekerov

Koensgen²,

Rosenthal³

et al. 2009

Mol Med Rep

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Abstract. The aim of the present study was to evaluate the expression of topoisomerase iiα (ToP2a) and Her-2 in tumor epithelial and adjacent stromal cells in ovarian cancer (ovca). immunohistochemistry for ToP2a and Her-2 was performed on 50 ovca specimens from the Tumor Bank of ovarian cancer, and was correlated to established clinicopathological parameters. ToP2a was expressed in 98% and Her-2 in 52% of the ovca specimens. Moderate expression of ToP2a was detected in 72% of the adjacent stromal cells. ToP2a and Her-2 were strongly expressed in the tumor epithelial cells of primary ovca, but reduced in recurrent ovca. Stromal expression of ToP2a increased in recurrent ovca after platinum-based chemotherapy. in conclusion, distinct epithelial and stromal cell expression of ToP2a and Her-2 is a novel feature in the tumor biology of ovca. differential cellular expression of ToP2a in relation to previous chemotherapy probably reflects a modified activity of the 'stromal compartment' in drug resistance. Thus, analysis of ToP2a expression in tumor and stromal ovca cells can aid in identifying subgroups of patients who may have a more favorable response to chemotherapy. Introductionovarian cancer (ovca) has the highest mortality rate of all female gynaecological cancers, with an overall 5-year survival rate of approximately 30% (1,2). at the time of primary diagnosis, most patients have advanced stage disease (Figo iii/iv) (3,4). cytoreductive surgery is known to have a strong prognostic effect on survival (4-6). despite the initial high response rates of current standard chemotherapy with carboplatin and paclitaxel, most patients relapse and soon succumb to the disease due to tumor progression (1). unfortunately, the complex mechanisms of platinum resistance are still poorly understood (7). Thus, the confirmation of novel molecular factors is a promising strategy that may help to individualize chemotherapy for ovca.Topoisomerase iiα (ToP2a) is an important proliferation marker in solid cancer (8,9), with significant expression during the S and g2-M phases (9,10). ToP2a is also the cellular target of anticancer drugs such as etoposide and doxorubicin (11), and has been implicated in contributing to atypical multidrug resistance in ovca (12,13). nonetheless, it does not appear to predict resistance as strongly as other factors. only a few studies have evaluated ToP2a expression in ovca cells, most describing increased amplification in advanced tumor stages associated with poor clinical outcome (8).The Her-2 proto-oncogene is essential for tumor growth and proliferation, with a wide range of amplification in solid tumors (14-16). different ligands can bind through its extracellular segments, and can mediate intracellular signal transduction through tyrosine kinase activity. Her-2 is also a target for novel therapeutic approaches, such as trastuzumab, a recombinant antibody designed to block signaling through the Her-2 receptor. Her2 expression in ovca shows rates of 1.8-76%, but data related to its prognostic value ar...

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Section: Discussionmentioning

confidence: 46%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tumor- and stromal cell-specific expression of topoisomerase IIα and HER-2/neu in primary and recurrent ovarian cancer: Results of a prospective study

Chekerov

Koensgen²,

Rosenthal³

et al. 2009

Mol Med Rep

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“…Because of the physical proximity to ErbB-2, copy number aberrations may also occur in the topoIIa gene, which may be related to the altered chemosensitivity to topoII inhibitors (Jarvinen and Liu, 2006). Our results show that xanafide sensitivity was not correlated with expression levels of both topoisomerase II a and b.…”

Section: Discussionmentioning

confidence: 61%

Comparative analysis of xanafide cytotoxicity in breast cancer cell lines

Alami

Paterson²,

Bélanger

et al. 2007

Br J Cancer

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Xanafide, a DNA-intercalating agent and topoisomerase II inhibitor, has previously demonstrated comparable cytotoxicity to the parent drug amonafide (NSC 308847). The current study was conducted to investigate further the anti-proliferative effects of xanafide in human breast cancer cell lines, in vitro and in vivo. The in vitro activity of xanafide against MCF-7, MDA-MB-231, SKBR-3 and T47D cell lines was compared to that of paclitaxel, docetaxel, gemcitabine, vinorelbine and doxorubicin. In MCF-7, xanafide demonstrated comparable total growth inhibition (TGI) concentrations to the taxanes and lower TGI values than gemcitabine, vinorelbine and doxorubicin. MCF-7 (oestrogen receptor (ER) þ /p53 wild-type) was the most sensitive cell line to xanafide. MDA-MB-231 and SKBR-3 exhibited similar sensitivity to xanafide. T47 D (ER þ /p53 mutated), showed no response to this agent. The in vivo activity of xanafide was further compared to that of docetaxel in MCF-7 and MDA-MB-231 cell lines using the hollow fibre assay. Xanafide was slightly more potent than docetaxel, at its highest dose in MCF-7 cell line, whereas docetaxel was more effective than xanafide in MDA-MB-231 cell line. Our results show that there is no relationship between sensitivity of these cell lines to xanafide and cellular levels of both isoforms of topoisomerase II and suggest that ER and p53 status and their crosstalk may predict the responsiveness or resistance of breast cancer patients to xanafide.

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The genomic profile of HER2‐amplified breast cancers: the influence of ER status

Marchiò

Natrajan

Shiu

et al. 2008

The Journal of Pathology

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Expression profiling studies have suggested that HER2-amplified breast cancers constitute a heterogeneous group that may be subdivided according to their ER status: HER2-amplified ER-positive breast carcinomas that fall into the luminal B cluster; and HER2-amplified ER-negative cancers which form a distinct molecular subgroup, known as the erbB2 or HER2 subgroup. ER-negative breast cancer differs significantly from ER-positive disease in the pattern, type, and complexity of genetic aberrations. Here we have compared the genomic profiles of ER-positive and ER-negative HER2-amplified cancers using tiling path microarray-based comparative genomic hybridization (aCGH). Validation of the differentially amplified regions was performed in an independent series of 70 HER2-amplified breast cancers. Although HER2-amplified cancers had remarkably complex patterns of molecular genetic aberrations, ER-positive and ER-negative HER2-amplified breast carcinomas shared most molecular genetic features as defined by aCGH. Genome-wide Fisher's exact test analysis revealed that less than 1.5% of the genome was significantly differentially gained or lost in ER-positive versus ER-negative HER2-amplified cancers. However, two regions of amplification were significantly associated with ER-positive carcinomas, one of which mapped to 17q21.2 and encompassed GJC1, IGFBP4, TNS4, and TOP2A. Chromogenic in situ hybridization analysis of an independent validation series confirmed the association between ER status and TOP2A amplification. In conclusion, although hormone receptor status does not determine the overall genetic profile of HER2-amplified breast cancers, specific genetic aberrations may be characteristic of subgroups of HER2 breast cancers.

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Simultaneous Amplification of HER-2 (ERBB2) and Topoisomerase IIα (TOP2A) Genes - Molecular Basis for Combination Chemotherapy in Cancer

Cited by 56 publications

References 171 publications

Tumor- and stromal cell-specific expression of topoisomerase IIα and HER-2/neu in primary and recurrent ovarian cancer: Results of a prospective study

Tumor- and stromal cell-specific expression of topoisomerase IIα and HER-2/neu in primary and recurrent ovarian cancer: Results of a prospective study

Comparative analysis of xanafide cytotoxicity in breast cancer cell lines

The genomic profile of HER2‐amplified breast cancers: the influence of ER status

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