Abstract 1703: Importance of pregnane X receptor (PXR) and P-glycoprotein (MDR1) to tamoxifen response and endoxifen disposition
Authors: Teft Wendy A. , Mansell Sara E. , Kim Richard B. 
Published: June 2012

Tamoxifen, a widely prescribed anti-estrogen for treating estrogen receptor positive breast cancer, is a prodrug which requires bioactivation by cytochrome P450 (CYP) enzymes 2D6 and 3A4 to generate the active metabolite, endoxifen. One obstacle to optimal tamoxifen therapy is the emergence of acquired endocrine resistance during therapy. Although resistance may be multifactorial, studies have shown reduced intra-tumour tamoxifen concentrations in patients with acquired resistance, suggesting the involvement of drug transporters. Tamoxifen is known to induce the expression of the nuclear hormone receptor pregnane X receptor (PXR), which we have shown to be upregulated in breast tumour cells compared with normal adjacent tissue. PXR is also known to regulate the expression of drug transporters including the efflux pump P-glycoprotein (MDR1). Together, we hypothesize that an individual's response to tamoxifen therapy may depend on the interplay between PXR and MDR1.

Although, MDR1 does not transport tamoxifen, its role in mediating transport of endoxifen is unknown. Therefore, we assessed the ability of MDR1 to transport endoxifen in vitro by comparing endoxifen flux using a polarized model system of LLCPK cells and LLCPK cells over-expressing human MDR1. In contrast to LLCPK cells, we observed a markedly higher transport of endoxifen in the basal to apical direction of LMDR1 cells, which was abrogated in the presence of the potent and specific MDR1 inhibitor LY335979. To validate the in vivo importance of MDR1 to endoxifen disposition, plasma and tissue concentrations were determined in Mdr1a deficient mice after oral administration of endoxifen. Plasma endoxifen levels did not significantly differ between wildtype and Mdr1a deficient mice. However, brain concentrations of endoxifen were nearly 20-fold higher in Mdr1a deficient mice compared to wildtype mice. Together, these data indicate that endoxifen is a substrate of MDR1. As MDR1 can be overexpressed in some breast tumours, variation in expression and function of this transporter may alter the attained intra-tumour concentration of endoxifen, which may manifest as aberrant clinical response to tamoxifen.

We are further investigating the contribution of PXR to the transcriptional regulation of MDR1 and its impact on cellular retention of endoxifen in breast cancer cells. To do this we will utilize the ability of tamoxifen to induce MDR1 expression through PXR activation in breast cancer cell lines and correlate the effect of MDR1 on the intracellular retention of tamoxifen and endoxifen. Finally, we plan to analyze breast tumour tissue from tamoxifen treated and non-treated patients to better understand the role of PXR and MDR1 to clinical response. Accordingly, activation of PXR by tamoxifen and subsequent induction of MDR1 may be an important prognostic factor for patients at risk for tamoxifen resistance.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1703. doi:10.1158/1538-7445.AM2011-1703