Transcription Factor Nkx-2.5 Induces Sodium/Iodide Symporter Gene Expression and Participates in Retinoic Acid- and Lactation-Induced Transcription in Mammary Cells

• DOI: 10.1128/mcb.24.18.7863-7877.2004
• Publication Date: 2004-08-31T00:08:05Z
• Authors: Monica Dentice; Cristina Luongo; Antonia Elefante; Romina Romino; Raffaele Ambrosio; Mario Vitale; Guido Rossi; Gianfranco Fenzi; Domenico Salvatore
• Keywords: Homeodomain Proteins; 0301 basic medicine; Binding Sites; Base Sequence; Symporters; Gene Expression; Breast Neoplasms; DNA, Neoplasm; Rats; 3. Good health; 03 medical and health sciences; Pregnancy; Cell Line, Tumor; Homeobox Protein Nkx-2.5; Mutagenesis, Site-Directed; Animals; Humans; Lactation; Female; RNA, Messenger; RNA, Neoplasm; Promoter Regions, Genetic; HeLa Cells

The sodium/iodide symporter (NIS) is a plasma membrane protein that mediates active iodide transport in thyroid and mammary cells. It is a prerequisite for radioiodide treatment of thyroid cancer and a promising diagnostic and therapeutic tool for breast cancer. We investigated the molecular mechanisms governing NIS expression in mammary cells. Here we report that Nkx-2.5, a cardiac homeobox transcription factor that is also expressed in the thyroid primordium, is a potent inducer of the NIS promoter. By binding to two specific promoter sites (N2 and W), Nkx-2.5 induced the rNIS promoter (about 50-fold over the basal level). Interestingly, coincident with NIS expression, Nkx-2.5 mRNA and protein were present in lactating, but not virgin, mammary glands in two human breast cancer samples and in all-trans retinoic acid (tRA)-stimulated MCF-7 breast cancer cells. A cotransfected dominant-negative Nkx-2.5 mutant abolished tRA-induced endogenous NIS induction, which shows that Nkx-2.5 activity is critical for this process. Remarkably, in MCF-7 cells, Nkx-2.5 overexpression alone was sufficient to induce NIS and iodide uptake. In conclusion, Nkx-2.5 is a novel relevant transcriptional regulator of mammary NIS and could thus be exploited to manipulate NIS expression in breast cancer treatment strategies.