Transcription factor Nkx-2.5 induces sodium/iodide symporter gene expression and participates in retinoic acid- and lactation-induced transcription in mammary 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.
Dentice
Monica
M
Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli Federico II, Naples, Italy.
Luongo
Cristina
C
Elefante
Antonia
A
Romino
Romina
R
Ambrosio
Raffaele
R
Vitale
Mario
M
Rossi
Guido
G
Fenzi
Gianfranco
G
Salvatore
Domenico
D
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006367:HeLa Cells; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D007774:Lactation / Q000235:genetics / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D051381:Rats; D027981:Symporters / Q000235:genetics*; D013961:Thyroid Gland / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology; D000099209:Sodium-Iodide Symporters
D004273:DNA, Neoplasm; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D027981:Symporters; D014157:Transcription Factors; D014212:Tretinoin; D000099209:Sodium-Iodide Symporters; C095552:NKX2-5 protein, human