title: Expression of sulfotransferase isoform 1A1 (SULT1A1) in breast cancer cells significantly increases 4-hydroxytamoxifen-induced apoptosis.
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.
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Mercer
authors.forename: Eugene O
authors.initials: EO
authors.lastname: Apostolov
authors.forename: Goncalo
authors.initials: G
authors.lastname: Gamboa da Costa
authors.forename: Xinfeng
authors.initials: X
authors.lastname: Yu
authors.forename: Patrick
authors.initials: P
authors.lastname: Lang
authors.forename: Dean W
authors.initials: DW
authors.lastname: Roberts
authors.forename: Warren
authors.initials: W
authors.lastname: Davis
authors.forename: Alexei G
authors.initials: AG
authors.lastname: Basnakian
authors.forename: Fred F
authors.initials: FF
authors.lastname: Kadlubar
authors.forename: Susan A
authors.initials: SA
authors.lastname: Kadlubar