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Int J Mol Epidemiol Genet 2010;1(2):92-103.

Original Article
Expression of sulfotransferase isoform 1A1 (SULT1A1) in breast cancer cells
significantly increases 4-hydroxytamoxifen-induced apoptosis

Kelly E. Mercer, Eugene O. Apostolov, Goncalo Gamboa da Costa, Xinfeng Yu, Patrick Lang, Dean W. Roberts, Warren Davis,
Alexei G. Basnakian, Fred F. Kadlubar, Susan A. Kadlubar

College of Public Health, Department of Environment and Occupational Health, University of Arkansas for Medical
Sciences, Little Rock, Arkansas 72205, USA, Department of Pharmacology and Toxicology, University of Arkansas for
Medical Sciences, Little Rock, Arkansas, 72205, USA, Centro de Química Estrutural, Complexo I, Instituto Superior
Técnico, Av. Rovisco Pais, 1049-001, Lisboa, Portugal, Department of Pediatric Pharmacology, University of Arkansas
for Medical Sciences, Little Rock, Arkansas, 72205, USA, Roswell Park Cancer Institute, Buffalo, New York 14623, USA

Received October 12, 2009, accepted January 20, 2010, available online: January 30, 2010

Abstract: Previously, we reported a strong association of the high activity SULT1A1*1 allele and overall survival of patients
receiving tamoxifen therapy, indicating that sulfation of 4-hydroxytamoxifen (4-OHT) via SULT1A1 may contribute to the
therapeutic efficacy of tamoxifen treatment. In most, but not all cases, sulfation is considered to be an elimination pathway;
therefore we sought to define the biological mechanism by which increased sulfation of tamoxifen could provide a therapeutic
benefit. We compared the antiproliferative and apoptotic responses between MCF7-SULT1A1 expressing cells and control
MCF7 pcDNA3 cells when treated with 4-OHT. We observed a greater than 30% decrease in cell proliferation in MCF7-
SULT1A1 expressing cells at physiological concentrations of 4-OHT, and significant cell death in SULT1A1-expressing cells
treated with 2μM 4-OHT for 48 hours compared to control cells (p<0.05). Within 24 hours of drug treatment, an 80% increase in
apoptosis in SULT1A1-expressing cells was apparent when compared to similarly treated cells that did not express SULT1A1.
We also observed an increase in endonuclease G, the primary endonuclease expressed in ER-dependent breast cancer cells,
which participates in caspaseindependent apoptosis. These data confirm that SULT1A1-mediated biotransformation of 4-OHT
is important in the efficacy of 4-OHT cytotoxicity in breast tumors, and reveals a potential role for sulfated metabolites in the
efficacy of tamoxifen therapy.(IJMEG910001).

Key words: SULT1A1, tamoxifen, apoptosis, genotype

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Address all correspondence to:
Susan Kadlubar, PhD
University of Arkansas for Medical Sciences
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