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¹ Department of Medicine and
² Department of Environmental and Occupational Medicine, University of Medicine and Dentistry of New Jersey – Robert Wood Johnson Medical School, New Brunswick, NJ 08903, USA
³ Environmental and Occupational Health Sciences Institute and
⁴ Department of Oncology, Lombardi Cancer Center, Georgetown University, Washington DC 20057, USA
⁵ The Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA

(Requests for offprints should be addressed to T Thomas, Clinical Academic Building, Room 7092, UMDNJ – Robert Wood Johnson Medical School, 125 Paterson Street, New Brunswick, New Jersey 08903, USA; Email: thomasth{at}UMDNJ.edu)

We studied the effects of 2-methoxyestradiol (2-ME₂) and 16-hydroxyestrone (16-OHE₁), two metabolites of estradiol (E₂), on DNA synthesis, cell cycle progression and cyclin D1 protein levels in estrogen receptor-positive MCF-7 cells. E₂ and 16-OHE₁ stimulated DNA synthesis, and 2-ME₂ inhibited the stimulatory effects of these agents. E₂ and 16-OHE₁ stimulated the progression of cells from G₁ to S phase and this effect was attenuated by 2-ME₂. Western blot analysis showed that E₂ and 16-OHE₁ increased cyclin D1 protein level by about fourfold compared with control. 2-ME₂ had no significant effect on cyclin D1; however, it prevented the accumulation of cyclin D1 in the presence of E₂ and 16-OHE₁. Cells transfected with a cyclin D1 reporter gene and treated with E₂ or 16-OHE₁ showed 7- and 9.5-fold increase respectively in promoter activity compared with control. This activity was significantly inhibited by 2-ME₂. Cyclin D1 transactivation was mediated by the cAMP response element (CRE) region, which binds activating transcription factor 2 (ATF-2). DNA affinity assay showed 2.5- and 3.5-fold increases in ATF-2 binding to CRE in the presence of E₂ and 16-OHE₁ respectively. The binding of ATF-2 was inhibited by the presence of 2-ME₂. These results show that 2-ME₂ can downregulate cyclin D1 and thereby cell cycle progression by a mechanism involving the disruption of ATF-2 binding to cyclin D1 promoter.

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