SULT1A1 Genetic Variation and Tamoxifen Response in Vitro and ex Vivo

Abstract

Sulfotransferase isoform 1A1 (SULT1A1) participates in the metabolism of a plethora of endo- and xenobiotic compounds. Inter-individual variability in the catalytic activity of this enzyme has historically been examined in platelets for their relative ease of access as a surrogate of liver activity, the body’s major metabolic organ. We proposed to study SULT1A1 activity in a novel model, immortalized lymphoblastoid cell lines (LCLs). This cell type can be grown in culture, whereas platelets cannot. Activity levels between platelets and LCLs were found to be highly correlated, validating the use of immortalized lymphocytes as a renewable surrogate of liver SULT1A1 activity data (Chapter I).

SULT1A1 metabolizes 4-hydroxytamoxifen (4-OHT), an active metabolite of the anti-breast cancer prodrug tamoxifen (TAM). Pharmacogenetic studies involving TAM therapy and SULT1A1 genetic variants shown to have functional consequences on the translated SULT1A1 protein have reported conflicting results. Biomarkers to predict favorable outcomes in patients treated with TAM therapy are lacking. We hypothesized that SULT1A1 copy number variations and single nucleotide polymorphisms would be able to serve as biomarkers of response to 4-OHT in LCLs in vitro and to TAM treatment ex vivo. When LCLs were treated with 4-OHT, variants of SULT1A1 had no effect on influencing response to treatment (Chapter I). Because we hypothesized that variations in SULT1A1 protein expression levels would serve as a biomarker of recurrence ex vivo, we used tissue microarrays to assess the level of SULT1A1 protein in tumors of breast cancer patients treated with TAM and enrolled in the Danish Breast Cancer Cooperative Group. After assigning protein expression levels into quintiles of positivity we found that SULT1A1 protein expression level was not associated with recurrence of disease (Chapter II).

Our findings suggest that LCLs are a suitable model to investigate SULT1A1 phenotype. However, results from the ex vivo study corroborated the findings of the in vitro cell culture studies in that SULT1A1 was not found to be a reliable biomarker for predicting breast cancer recurrence after TAM treatment. LCLs will likely be useful in examining variation in metabolic pathways for other enzymes and other drugs.