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Departments of ¹ Structural and Cellular Biology and ² Biochemistry, Tulane University School of Medicine, New Orleans, Louisiana and ³ Department of Cancer Chemoprevention, Roswell Park Cancer Institute, Buffalo, New York

Requests for reprints: Brian G. Rowan, Department of Structural and Cellular Biology, SL49, Tulane University School of Medicine, 1430 Tulane Avenue, New Orleans, LA 70112. Phone 504-988-1365; Fax: 504-988-1687. E-mail: browan{at}tulane.edu

Tamoxifen, a selective estrogen receptor (ER) modulator, is the most widely prescribed hormonal therapy treatment for breast cancer. Despite the benefits of tamoxifen therapy, almost all tamoxifen-responsive breast cancer patients develop resistance to therapy. In addition, tamoxifen displays estrogen-like effects in the endometrium increasing the incidence of endometrial cancer. New therapeutic strategies are needed to circumvent tamoxifen resistance in breast cancer as well as tamoxifen toxicity in endometrium. Organic selenium compounds are highly effective chemopreventive agents with well-documented benefits in reducing total cancer incidence and mortality rates for a number of cancers. The present study shows that the organic selenium compound methylseleninic acid (MSA, 2.5 µmol/L) can potentiate growth inhibition of 4-hydroxytamoxifen (10^–7 mol/L) in tamoxifen-sensitive MCF-7 and T47D breast cancer cell lines. Remarkably, in tamoxifen-resistant MCF-7-LCC2 and MCF7-H216 breast cancer cell lines and endometrial-derived HEC1A and Ishikawa cells, coincubation of 4-hydroxytamoxifen with MSA resulted in a marked growth inhibition that was substantially greater than MSA alone. Growth inhibition by MSA and MSA + 4-hydroxytamoxifen in all cell lines was preceded by a specific decrease in ER mRNA and protein without an effect on ERß levels. Estradiol and 4-hydroxytamoxifen induction of endogenous ER-dependent gene expression (pS2 and c-myc) as well as ER-dependent reporter gene expression (ERE₂e1b-luciferase) was also attenuated by MSA in all cell lines before effect on growth inhibition. Taken together, these data strongly suggest that specific decrease in ER levels by MSA is required for both MSA potentiation of the growth inhibitory effects of 4-hydroxytamoxifen and resensitization of tamoxifen-resistant cell lines.

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.

⁴ Y.M. Shah, et al. Attenuation of Estrogen Receptor (ER) Signaling by Selenium in Breast Cancer Cells via Downregulation of ER Gene Expression. Breast Cancer Research and Treatment, in press.

⁵ F. Jones, et al. An oncogenic isoform of ERBB2/HER2 associated with metastatic breast cancer, submitted for publication.

Received 2/11/05; revised 5/27/05; accepted 6/14/05.

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