Overexpression of MDM2 in MCF-7 promotes both growth advantage and p53 accumulation in response to estradiol

The overexpression of the oncogene product MDM2 is often observed in human breast cancer cells, especially in estrogen receptor (ER)-positive ones. To study the role of MDM2 protein in ER-positive breast cancer, me have estab lished cell lines derived from MCF-7 which stably express increased and dec reased levels of MDM2 by transfection of a mammalian expression vector cont aining human mdm2 cDNA in sense and antisense orientations, respectively, I nterestingly, MDM2 overexpression in MCF-7 cells afforded a remarkable grow th advantage under estradiol (E-2)-supplemented condition. Then, we analyze d the expression of p53, which is an important regulator of growth and the cell cycle, Unexpectedly, the p53 accumulation induced by E-2 was remarkabl y higher in MCF-7 cells stably overexpressing MDM2 than in the parent MCF-7 cells, On the other hand, reduction of MDM2 suppressed the E-2-induced inc rease in p53 protein. Moreover, mdm2 antisense oligonucleotides prevented E -2-induced accumulation of p53, In the steady state, the cellular levels of p53 sere also correlated with those of MDM2. These interactions are not co nsistent with the well-known role of MDM2, which acts as a negative regulat or for p53 by inhibiting its function and promoting its rapid degradation. These results suggest that MDM2 may regulate the expression of p53 in the s teady state and in response to E-2 in breast cancer cells, and imply a nove l and important role of MDM2 during breast carcinogenesis.