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).
Address all correspondence to: Susan Kadlubar, PhD University of Arkansas for Medical Sciences 4301 W. Markham, #820 Little Rock, AR 72205 Tel: 501-526-7957, Fax: 501-526-6650 Email: firstname.lastname@example.org