Tamoxifen Induces Expression of Immune Response–Related Genes in Cultured Normal Human Mammary Epithelial Cells

Abstract

Use of tamoxifen is associated with a 50% reduction in breast cancer incidence and an increase in endometrial cancer incidence. Here, we documented tamoxifen-induced gene expression changes in cultured normal human mammary epithelial cells (strains 5, 16, and 40), established from tissue taken at reduction mammoplasty from three individuals. Cells exposed to 0, 10, or 50 Mmol/L of tamoxifen for 48 hours were evaluated for (E)-A-(deoxyguanosine-N 2 -yl)-tamoxifen (dG-N 2 -TAM) adduct formation using TAM-DNA (DNA modified with dG-N 2 -TAM) chemiluminescence immunoassay, gene expression changes using National Cancer Institute DNAoligonucleotide microarray, and real-time PCR. At 48 hours, cells exposed to 10 and 50 Mmol/L of tamoxifen were 85.6% and 48.4% viable, respectively, and there were no measurable dG-N 2 -TAM adducts. For microarrays, cells were exposed to 10 Mmol/L of tamoxifen and genes with expression changes of >3-fold were as follows: 13 genes up-regulated and 1 downregulated for strain 16; 17 genes up-regulated for strain 5, and 11 genes up-regulated for strain 40. Interferon-inducible genes (IFITM1, IFIT1, MXI, and GIP3), and a potassium ion channel (KCNJ1) were up-regulated in all three strains. No significant expression changes were found for genes related to estrogen or xenobiotic metabolism. Real-time PCR revealed the upregulation of IFNA1 and confirmed the tamoxifen-induced upregulation of the five other genes identified by microarray, with the exception of GIP3 and MX1, which were not upregulated in strain 40. Induction of IFN-related genes in the three normal human mammary epithelial cell strains suggests that, in addition to hormonal effects, tamoxifen exposure may enhance immune response in normal breast tissue.

Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

“…Combined examination of those genes significantly deregulated during MCF7-LTED adaptation and those for which expression change is reported shortly after initiation of endocrine therapy is important, given the relevance of these early changes in the prediction of subsequent responses (Miller et al, 2007;Schild-Hay et al, 2009). Our data recapitulate the early transcriptional changes but, given the dynamic behavior of these alterations, also suggest that caution should be taken when assessing their relevance to the overall benefit of the treatment in the clinical setting.…”

Aberrant Regulation of the BST2 (Tetherin) Promoter Enhances Cell Proliferation and Apoptosis Evasion in High Grade Breast Cancer Cells

“…Our data demonstrates a direct functional role of BST2 in the establishment of therapeutic resistance to an ER antagonist. Among changes in the expression of several other genes, profiling studies of tamoxifen-treated normal human mammary epithelial cell cultures have noted induction of BST2 [30]. Further work is needed to decipher the molecular mechanism of BST2-mediated drug resistance, for example how BST2 interacts with, and influences the ER signaling cascade, could be illuminating.…”

Tetrabromobisphenol A activates the hepatic interferon pathway in rats

“…MX1 and interferon regulatory factors) in model systems (Dabydeen et al, 2015; Fawzy et al, 2012; Schild-Hay et al, 2009). Exposure of myeloid cells to a related chemical, bisphenol A, also stimulated interferon signaling (Panchanathan et al, 2015).…”