RELATIONSHIP BETWEEN EXPRESSION OF TOPOISOMERASE-II ISOFORMS AND INTRINSIC SENSITIVITY TO TOPOISOMERASE-II INHIBITORS IN BREAST-CANCER CELL-LINES

Topoisomerase II is a key target for many anti-cancer drugs used to tr eat breast cancer. In human cells there are two closely related, but d ifferentially expressed, topoisomerase II isoforms, designated topoiso merase II alpha and beta. Here, we report the production of a new poly clonal antibody raised against a fragment of the C-terminal domain of the 180 kDa form of topoisomerase II (the beta isoform), which does no t cross-react with the 170 kDa form (the alpha isoform). Using this an tibody, together with a polyclonal antibody specific for the 170 kDa i soform of topoisomerase II, we have examined the relationship between the sensitivity of a panel of human breast cancer cell lines to differ ent classes of topoisomerase II inhibitors and cellular levels of the topoisomerase II alpha and beta proteins. We found that sensitivity to amsacrine showed a correlation with the level of expression of topois omerase II alpha protein, and that sensitivity to etoposide showed a s imilar correlation with the level of expression of topoisomerase II be ta protein. There was also a relationship between sensitivity of these cell lines to mitoxantrone and the cellular Level of both isoforms of topoisomerase II. No relationship was found between the level of mRNA for topoisomerase II alpha or beta, and either sensitivity of breast cancer cell lines to topoisomerase II inhibitors or the level of topoi somerase II protein expression.