Context: All-trans retinoic acid (tRA) induces differentiation in MCF-7 breast cancer cells, stimulates sodium/iodide symporter (NIS) gene expression, and inhibits cell proliferation. Radioiodine administration after systemic tRA treatment has been proposed as an approach to image and treat some differentiated breast cancer.

Objective: To study the relative role of genomic and non-genomic pathways in tRA stimulation of NIS expression in MCF-7 cells.

Design: We inspected the human NIS gene locus for retinoic acid responsive elements and tested them for function. The effects of signal transduction pathway inhibitors were also tested in tRA-treated MCF-7 cells and TSH-stimulated FRTL-5 rat thyroid cells, followed by iodide uptake assay, quantitative RT-PCR of NIS, and cell cycle phase analysis.

Results: Multiple retinoic acid response elements around the NIS locus were identified by sequence inspection, but none of them was a functional tRA-induced element in MCF-7 cells. Inhibitors of the IGF1 receptor, JAK, and PI3K significantly reduced NIS mRNA expression and iodide uptake in tRA-stimulated MCF-7 cells, but not in FRTL-5 cells. An inhibitor of p38 MAPK significantly reduced iodide uptake in both tRA-stimulated MCF-7 cells and TSH-stimulated FRTL-5 cells. IGF1 and PI3K inhibitors did not significantly reduce the basal NIS mRNA expression in MCF-7 cells. Despite the chronic inhibitory effects on cell proliferation, tRA did not reduce the S-phase distribution of MCF-7 cells during the period of NIS induction.

Conclusion: The IGF1 receptor/PI3K pathway mediates tRA-stimulated NIS expression in MCF-7, but not in FRTL-5 thyroid cells.