DRUG-RESISTANT BREAST-CANCER CELLS FREQUENTLY RETAIN EXPRESSION OF A FUNCTIONAL WILD-TYPE P53 PROTEIN

Abnormalities in the p53 tumor suppressor gene have been shown to affe ct cellular processes related to cell cycle control and gene amplifica tion, In this study we compare the status and function of wild-type p5 3 in MCF-7 breast cancer cells with sublines selected for resistance t o chemotherapeutic agents having different mechanisms of action. Subli nes that were resistant to melphalan, pyrazafurin, mitoxantrone, etopo side and PALA all retained expression of wild-type p53, Methotrexate-r esistant MCF-7 cells were unusual heterozygotes that expressed a wild- type and dominant, in-frame p53 deletion mutant and the doxorubicin-re sistant cells expressed only mutant p53, Analysis of the G1 checkpoint after treatment with ionizing radiation revealed that the pyrazafurin -, melphalan- and mitoxantrone-resistant cells arrested strongly in G1 , The etoposide-and PALA-resistant cells had an intermediate G1 arrest phenotype and the methotrexate- and doxorubicin-resistant cells had a minimal G1 arrest phenotype. mRNA and protein analyses of downstream effector genes, including p21(CIP1/Waf1), mdm2, Gadd 45 and the retino blastoma protein, did not entirely differentiate sublines having a str ong versus intermediate G1 arrest phenotype, Neither the p53 status no r the strength of the G1 arrest could be correlated with cell survival after ionizing radiation, When drug-sensitive MCF-7 cells were treate d with the same chemotherapeutic agents, p53 and p21(CIP1/Waf1) levels increased between 2-and 14-fold. Together these data suggest that oth er cellular factors likely play a role in overcoming the inhibitory ef fects of ionizing radiation on p53 in drug-resistant breast cancer cel ls.