¹Department of Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey, NJ 08903, USA

²Department of Environmental & Community Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey, NJ 08903, USA

³Department of Biochemistry, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey, NJ 08903, USA

⁴The Environmental and Occupational Health Sciences Institute, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey, NJ 08903, USA

⁵The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey, NJ 08903, USA

⁶Center for Advanced Biotechnology and Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey, NJ 08903, USA

⁷Nutritional Sciences Graduate Program, Rutgers-The State University of New Jersey, New Brunswick, New Jersey, NJ 08903, USA

⁸Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, Kentucky, KY 40292, USA

⁹Faculty of Pharmaceutical Sciences, Josai University, Sakado, Saitama 350-02, Japan

Correspondence to: T Thomas, 125 Paterson Street, Clinical Academic Building, Room 7090, New Brunswick, NJ 08901, USA

The natural polyamines -putrescine, spermidine, and spermine- are essential for cell growth and differentiation. Polyamines are involved in several gene regulatory functions, although their mechanism(s) of action has not been elucidated. We investigated the role of polyamines in the function of NF-B and estrogen receptor- (ER), two transcription factors implicated in breast cancer cell proliferation and cell survival, using MCF-7 breast cancer cells. We found that spermine facilitated the binding of ER and NF-B to estrogen response element (ERE)- and NF-B response element (NRE), respectively, and enhanced ER-mediated transcriptional activation in transient transfection experiments. We also found that the association of the co-regulatory protein CBP/p300 with ER and NF-B was increased by spermine treatment of MCF-7 cells. Spermine also increased the nuclear translocation of NF-B compared to the control. In contrast, treatment of MCF-7 cells with polyamine analogs, BE-3-4-3 and BE-3-3-3, resulted in transcriptional inhibition of both ERE- and NRE-driven reporter plasmids. In addition, polyamine analogs inhibited the association of ER and NF-B with CBP/p300 and were unable to facilitate nuclear translocation of NF-B. APO-BRDU assay demonstrated that polyamine analogs induced apoptosis, with a loss of the anti-apoptotic protein Bcl-2. These data show a gene regulatory function of polyamines involving transcriptional activation of ER and NF-B, potentially leading to the up-regulation of genes involved in breast cancer cell proliferation. Our results with BE-3-4-3 and BE-3-3-3 suggest that down-regulation of ER- and NF-B-regulated genes is a possible mechanism for the action of polyamine analogs in inducing apoptosis of breast cancer cells. Oncogene (2001) 20, 1715-1729.

polyamines; nuclear factor B; estrogen receptor; breast cancer