Co-amplification of erbB2, topoisomerase II α and retinoic acid receptor α genes in breast cancer and allelic loss at topoisomerase I on chromosome 20

Keith, W. Nicol; Douglas, Fiona; Wishart, Gordon; McCallum, H.; George, W.D.; Kaye, SB; Brown, Robert

doi:10.1016/0959-8049(93)90022-8

Cited by 66 publications

(32 citation statements)

References 20 publications

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“…We have previously shown that the region of amplification found in primary breast tumours encompasses at least three loci including ERBB2, RARa and topoisomerase IIa. The PKCa locus was found to be outside the region of amplification showing that the increased copy number of the three genes is due to amplification rather than aneuploidy (Keith et al, 1993). We have also previously shown that the lung adenocarcinoma cell line, CALU3, has co-amplification ERBB2 and topoisomerase IIa (Keith et al, 1992).…”

Section: Discussionmentioning

confidence: 81%

“…The adenocarcinoma cell line CALU3 has the co-amplification of topoisomerase II alpha and ERBB2 sequences characteristic of a subset of breast adenocarcinomas (Keith et al, 1992(Keith et al, , 1993 (Figures 3 and 4). Two distinct antibodies were used to examine alpha expression by Western and immunofluorescence therefore confirming by independent methods that the isoform detected is indeed the alpha product.…”

Section: Discussionmentioning

confidence: 99%

“…Molecular changes at topoisomerase loci which result in altered expression are therefore important and recently it has been shown that the topoisomerase II alpha gene is co-amplified along with ERBB2 in a subset of breast adenocarcinomas (Keith et al, 1993).…”

mentioning

confidence: 99%

“…Due to the clinical use of topoisomerase II inhibitors (Muggia & Gill, 1991) the levels of expression in tumours may be important in determining the success of the treatment. Molecular changes at topoisomerase loci which result in altered expression are therefore important and recently it has been shown that the topoisomerase II alpha gene is co-amplified along with ERBB2 in a subset of breast adenocarcinomas (Keith et al, 1993).…”

mentioning

confidence: 99%

“…Polyclonal antiserum against topoisomerase II alpha was obtained from TopoGen (Columbus Ohio), the monoclonal antibody to topoisomerase II beta was kindly provided by Dr G.C.B. Astaldi Ricotti (Negri et al, 1992 (Keith et al, 1993). Densitometry was performed using a Molecular Dynamics laser scanning densitometer.…”

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confidence: 99%

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Expression of topoisomerase II alpha and beta in an adenocarcinoma cell line carrying amplified topoisomerase II alpha and retinoic acid receptor alpha genes

Coutts¹,

Plumb²,

Brown³

et al. 1993

Br J Cancer

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Summary Human topoisomerase II enzymes are targets for a number of widely used anticancer agents. We have analysed a lung adenocarcinoma cell line CALU3, which has co-amplified topoisomerase IIax and ERBB2 sequences, for the structure of the amplicon and for expression of both topoisomerase Ila and P. The al., 1989;Woessner et al., 1991). Recent studies have also indicated that the alpha and beta enzymes are sublocalised within the nucleus to the nucleoplasm and nucleoli respectively (Negri et al., 1992).Interest in topoisomerase II is due both to its essential catalytic activity in normal cells and that it is a key target for a group of anticancer agents including etoposide, doxorubicin and mAMSA (Takano et al., 1992;Liu, 1989 (Muggia & Gill, 1991) the levels of expression in tumours may be important in determining the success of the treatment. Molecular changes at topoisomerase loci which result in altered expression are therefore important and recently it has been shown that the topoisomerase II alpha gene is co-amplified along with ERBB2 in a subset of breast adenocarcinomas (Keith et al., 1993).We have previously shown that the lung adenocarcinoma cell line CALU3, has co-amplification of ERBB2 and topoisomerase Ilcc, (Keith et al., 1992). This cell line therefore provides a model to examine the role of topoisomerase Ila amplification and expression in drug sensitivity. We have now investigated the expression, localisation and enzymatic activity of both topoisomerase Ila and P in CALU3 and further characterised the amplicon containing the topoisomerase Ila gene. We show here that the amplified topoisomerase II alpha gene in CALU3 is expressed at a high level and that enzyme activity is inhibited by a topoisomerase II interactive drug. Immunofluorescence studies using antibodies against topoisomerase II alpha and beta show the alpha product to be expressed heterogeneously within the cell population. In contrast, the beta isoform is expressed in all cells and localised to the nucleolus. In addition, we show by fluorescence in situ hybridisation (FISH)

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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