The expression of p53 tumor suppressor gene in breast cancer cells is down-regulated by cytokine oncostatin M

Previously (J. Liu, et al., Cell Growth Differ., 8: 667-676, 1997), we show ed that oncostatin M (OM), a cytokine produced by activated T cells and mac rophages, inhibited the proliferation of breast cancer cells derived from s olid tumors and malignant effusions, OM-treated cells showed reduced growth rates and differentiated phenotypes, Because the p53 tumor suppressor prot ein plays an important role in cellular proliferation, we examined p53 prot ein expression in three OM-responsive breast cancer cell lines, MCF-7, MDA- MB231, and H3922. Western blot analysis showed that p53 protein levels in a ll three of the cell lines were decreased by OM treatment. Reduction of p53 protein was detected after 1 day of OM treatment and reached maximal suppr ession of 10-20% of control after 3 days in H3922 and 40% of control after 4 days in MCF-7 cells. A comparison of p53 mRNA in OM-treated cells versus untreated control cells showed that exposure to OM reduced the steady-state levels of p53 mRNA transcripts to an extent similar to that of the p53 pro tein levels. This observation suggests that the effect of OM on p53 protein expression does not occur at the posttranslational level. Nuclear run-on a ssays verified that OM decreased the number of actively transcribed p53 mRN As, which suggests a transcriptional regulatory mechanism. The effect of OM on p53 expression seems to be mediated through the extracellular signal-re gulated kinase (ERK) pathway, inasmuch as the inhibition of ERK activation with a specific inhibitor (PD98059) to the ERK upstream kinase mitogen/extr acellular-regulated protein kinase kinase abrogated the OM inhibitory activ ity on p53 expression in a dose-dependent manner. In addition to OM, we sho wed that the p53 protein expression in MCF-7 cells was also decreased by ph orbol 12-myristate 13-acetate treatment (PMA), Because both OM and PMA indu ce MCF-7 cells to differentiate, our data suggest that p53 expression in br east cancer cells is down-regulated during the differentiation process.