ALTERED GENE-EXPRESSION IN DRUG-RESISTANT HUMAN BREAST-CANCER CELLS

It is increasingly recognized that drug-resistant cells undergo transi tions not directly linked to ''classical'' drug resistance, We examine d the expression of growth factors, growth factor receptors, and the e strogen receptor in 17 drug-resistant and 2 revertant human breast can cer sublines to provide an understanding of the phenotypic changes tha t occur and how these changes could affect the biology of the cell, Th ese sublines were derived from five parental human breast cancer cell lines (MCF-7, ZR75B, T47D, MDA-MB-231, and MDA-MB-453). The expression of estrogen receptor was absent or decreased in 6 of the 15 resistant MCF-7. ZR75B, and T47D sublines, Increases of as much as 49-fold comp ared to parental levels were observed in transforming growth factor al pha, epidermal growth factor receptor, c-erbB2, and/or c-erbB3 mRNA ex pression in 14 of the 17 resistant sublines, Altered amphiregulin and insulin-like growth factor-I receptor expression was observed in nine and four drug-resistant sublines, respectively, No major alterations w ere observed in epidermal growth factor and c-erbB4 expression, Few al terations were observed in two sublines derived from estrogen receptor -negative cells, Higher levels of phosphotyrosine residues were detect ed in a subset of the resistant sublines, indicating an increased tyro sine kinase activity in these cells, Interestingly, decreased growth r ates were observed in all of the sublines, despite up-regulated growth factor-related gene expression, Taken together, these data suggest th at loss of estrogen receptor, increased expression of growth factor pa thway genes, and decreased growth rate regularly occur in drug-resista nt breast cancer cells. Although we do not know whether the altered ex pression of growth factor pathway genes is linked as a cause or a cons equence of the reduced growth rate, it is well established that decrea sed growth rate confers drug resistance, These phenotypic changes in d rug-resistant human breast cancer cells could serve to initiate, suppo rt, or extend the drug resistance.