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

Shigehira Saji, Shigeru Nakashima, Shin Ichi Hayashi, Masakazu Toi, Shigetoyo Saji, Yoshinori Nozawa

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

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, we have established cell lines derived from MCF-7 which stably express increased and decreased levels of MDM2 by transfection of a mammalian expression vector containing human mdm2 cDNA in sense and antisense orientations, respectively. Interestingly, MDM2 overexpression in MCF-7 cells afforded a remarkable growth advantage under estradiol (E2-supplemented condition. Then, we analyzed the expression of p53, which is an important regulator of growth and the cell cycle. Unexpectedly, the p53 accumulation induced by E2 was remarkably higher in MCF-7 cells stably overexpressing MDM2 than in the parent MCF-7 cells. On the other hand, reduction of MDM2 suppressed the E2-induced increase in p53 protein. Moreover, mdm2 antisense oligonucleotides prevented E2-induced accumulation of p53. In the steady state, the cellular levels of p53 were also correlated with those of MDM2. These interactions are not consistent with the well-known role of MDM2, which acts as a negative regulator for p53 by inhibiting its function and promoting its rapid degradation. These results suggest that MDM2 may regulate the expression of p53 in the steady state and in response to E2 in breast cancer cells, and imply a novel and important role of MDM2 during breast carcinogenesis.

Original languageEnglish
Pages (from-to)210-218
Number of pages9
JournalJapanese Journal of Cancer Research
Volume90
Issue number2
DOIs
Publication statusPublished - 1999 Feb
Externally publishedYes

Keywords

  • Breast cancer
  • Estrogen receptor
  • MDM2
  • p53

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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