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Molecular and Cellular Biology, September 2004, p. 7863-7877, Vol. 24, No. 18
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.18.7863-7877.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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

Monica Dentice,1 Cristina Luongo,2 Antonia Elefante,2 Romina Romino,2 Raffaele Ambrosio,2 Mario Vitale,2 Guido Rossi,1 Gianfranco Fenzi,2 and Domenico Salvatore2*

Dipartimento di Biologia e Patologia Cellulare e Molecolare,1 Dipartimento di Endocrinologia ed Oncologia Molecolare e Clinica, Università di Napoli "Federico II," Naples, Italy2

Received 16 January 2004/ Returned for modification 3 March 2004/ Accepted 16 June 2004

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.

* Corresponding author. Mailing address: Department of Endocrinology and Molecular and Clinical Oncology, University of Naples "Federico II," Via S. Pansini 5, 80131 Naples, Italy. Phone: (39) 081-7463780. Fax: (39) 081-7463668. E-mail: domsalva{at}unina.it.

Molecular and Cellular Biology, September 2004, p. 7863-7877, Vol. 24, No. 18
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.18.7863-7877.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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