Tamoxifen induces expression of immune response-related genes in cultured normal human mammary epithelial cells.
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 micromol/L of tamoxifen for 48 hours were evaluated for (E)-alpha-(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 DNA-oligonucleotide microarray, and real-time PCR. At 48 hours, cells exposed to 10 and 50 micromol/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 micromol/L of tamoxifen and genes with expression changes of >3-fold were as follows: 13 genes up-regulated and 1 down-regulated 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 up-regulation of IFNA1 and confirmed the tamoxifen-induced up-regulation of the five other genes identified by microarray, with the exception of GIP3 and MX1, which were not up-regulated 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.
Schild-Hay
Laura J
LJ
Carcinogen-DNA Interactions Section, LCBG, CCR, National Cancer Institute, NIH, Bethesda, Maryland 20892-4255, USA.
Leil
Tarek A
TA
Divi
Rao L
RL
Olivero
Ofelia A
OA
Weston
Ainsley
A
Poirier
Miriam C
MC
D002478:Cells, Cultured; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D018736:DNA Adducts / Q000096:biosynthesis; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology; D005260:Female; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D011960:Receptors, Estrogen / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013629:Tamoxifen / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects* / Q000276:immunology*
D018736:DNA Adducts; D011960:Receptors, Estrogen; D013629:Tamoxifen; D004247:DNA