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.