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J. Biol. Chem., Vol. 281, Issue 28, 19055-19063, July 14, 2006

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Polyamine Analogues Down-regulate Estrogen Receptor Expression in Human Breast Cancer Cells^*

Yi Huang, Judith C. Keen¹, Allison Pledgie, Laurence J. Marton, Tao Zhu, Saraswati Sukumar, Ben Ho Park, Brian Blair, Keith Brenner, Robert A. Casero, Jr, and Nancy E. Davidson²

From the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231 and Cellgate Inc., Redwood City, California 94065

The critical role of polyamines in cell growth has led to the development of a number of agents that interfere with polyamine metabolism including a novel class of polyamine analogues, oligoamines. Here we demonstrate that oligoamines specifically suppress the mRNA and protein expression of estrogen receptor (ER) and ER target genes in ER-positive human breast cancer cell lines, whereas neither ER nor other steroid hormonal receptors are affected by oligoamines. The constitutive expression of a cytomegalovirus promoter-driven exogenous ER in ER-negative MDA-MB-231 human breast cancer cells was not altered by oligoamines, suggesting that oligoamines specifically suppress ER transcription rather than affect mRNA or protein stability. Further analysis demonstrated that oligoamines disrupted the DNA binding activity of Sp1 transcription factor family members to an ER minimal promoter element containing GC/CA-rich boxes. Treatment of MDA-MB-231 cells with the JNK-specific inhibitor SP600125 or expression of the c-Jun dominant negative inhibitor TAM67 blocked the oligoamine-activated JNK/c-Jun pathway and enhanced oligoamine-inhibited ER expression, suggesting that AP-1 is a positive regulator of ER expression and that oligoamine-activated JNK/AP-1 activity may antagonize the down-regulation of ER induced by oligoamines. Taken together, these results suggest a novel antiestrogenic mechanism for specific polyamine analogues in human breast cancer cells.

Received for publication, January 30, 2006 , and in revised form, April 3, 2006.

^* This work was supported by National Institutes of Health Grants P50CA88843, CA98454, and CA51085; Department of Defense Grants DAMD 17-03-1-0376 and W81XWH-04-1-0457; and funds from the Breast Cancer Research Foundation, the Flight Attendant Medical Research Institute (FAMRI), and the Avon Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Coriell Institute for Medical Research, Camden, New Jersey 08106.

² To whom correspondence should be addressed: Breast Cancer Program, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St., Rm. 409, Baltimore, MD 21231.Tel.: 410-955-8489; Fax: 410-614-4073; E-mail: davidna{at}jhmi.edu.

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				M. Sui, Y. Huang, B. H. Park, N. E. Davidson, and W. Fan Estrogen Receptor {alpha} Mediates Breast Cancer Cell Resistance to Paclitaxel through Inhibition of Apoptotic Cell Death Cancer Res., June 1, 2007; 67(11): 5337 - 5344. [Abstract] [Full Text] [PDF]