Induction of breast cancer resistance protein by the camptothecin derivative DX-8951f is associated with minor reduction of antitumour activity.

In the present study, we addressed the question of a putative relevance of Rho proteins in tumour progression by analysing their expression on protein and mRNA level in breast turnouts. We show that the level of RhoA, RhoB, Racl and Cdc42 protein is largely enhanced in all turnout samples analysed (n=15) as compared to normal tissues originating from the same individual. The same is true for [sup 32]P-ADP-ribosytation of Rho proteins which is catalysed by Clostridium botulinum exoenzyme C3. Also the amount of Rho-GDI and ERK2 as well as the level of overall [sup 32]P-GTP binding activity was turnout-specific elevated, yet to a lower extent than Rho proteins, Although the amount of Rho proteins was enhanced in tumours, most of them did not show changes in rho mRNA expression as compared to the corresponding normal tissue. Thus, elevated gene expression seems not to be the underlying mechanism of tumour-specific overexpression of Rho proteins. Sequence analysis of RhoA, RhoB, RhoC and Racl failed to detect any mutations in both the GTP-binding site and effector binding region, By analysing > 50 tumour samples, the amount of RhoA-like proteins (i,e, RhoA, B, C), but not of Racl, was found to significantly increase with histological grade and proliferation index. Rho protein expression was neither related to p53 nor to HER-2/neu oncogene status. Expression of rho mRNAs did not show a significant increase with histological grade. Overall the data show that (1) Rho proteins are overexpressed in breast tumours (2) overexpression is not regulated on the mRNA level (3) the expression level of RhoA-Iike proteins correlates with malignancy and (4) Rho proteins are not altered by mutation in breast tumours. [ABSTRACT FROM AUTHOR]