A paradigm for oncogene complementation in human breast cancer.
Multiple cellular oncogenes are amplified in malignant tumours, and it is possible to invoke gene dosage as a possible base for product activity. In vitro data have shown that two different oncogenes can cooperate in converting a normal cell into one that is tumorigenic. This suggested that multiple cooperative alterations might be involved in cancer progression. Breast cancers have a broad spectrum of clinical behaviours ranging from highly aggressive neoplasms to almost chronic diseases. Fifty months of clinical follow-up were studied in 143 patients with primary breast cancers. Uni- and multivariate analyses were performed in order to determine any synergistic effect of amplified c-myc, erbB-2 and int-2 genes on the disease-free state and overall survival. We showed that c-myc amplification was associated with early recurrence and shorter survival; in contrast, erbB-2 and int-2 extra copies resulted in later relapse events, especially in patients whose tumours showed a normal copy number of c-myc genes. This pointed out sequential activation of complex regulatory cascades within the cell. Such particular behaviour enabled us to categorize erbB-2 and int-2 oncogenes into a group showing delayed action, in contrast to c-myc involvement in rapid spread of the tumour. As expected, co-amplified c-myc and erbB-2 genes showed positive cooperation with respect to recurrence and shortening of overall survival. Finally, the harmful effects of amplified c-myc and erbB-2 oncogenes were dramatically increased in patient subgroups showing a normal copy number of the int-2 gene. Multivariate analysis was used to evaluate disease-free survival and to test for potential interactions of oncogene covariates. It pointed out multiple independent combinations which enabled us to define complementation groups with respect to clinical patient behaviour.
Roux-Dosseto
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URA CNRS 1175, Faculté de Médecine-Nord, Marseille, France.
Martin
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PM
D015139:Blotting, Southern; D001943:Breast Neoplasms / Q000235:genetics*; D004273:DNA, Neoplasm / Q000032:analysis*; D066246:ErbB Receptors; D005260:Female; D051518:Fibroblast Growth Factor 3; D005346:Fibroblast Growth Factors; D005500:Follow-Up Studies; D005784:Gene Amplification; D005816:Genetic Complementation Test; D006801:Humans; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D009857:Oncogenes; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc; D012189:Retrospective Studies
D004273:DNA, Neoplasm; C496444:FGF3 protein, human; D051518:Fibroblast Growth Factor 3; D011518:Proto-Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D005346:Fibroblast Growth Factors; D066246:ErbB Receptors