Research Focus

* Transcriptional Regulation of the Na+/I- Symporter (NIS) Gene in Lactating Mammary Gland and in Breast Cancer.
* Structure-function relationships in solute transporters.

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Department of Molecular Biology and Genetics

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Research Interests

Transcriptional Regulation of the Na+/I- Symporter (NIS) Gene in Lactating Mammary Gland and in Breast Cancer.

Iodide (I-) is an essential constituent of thyroid hormones (T3 and T4), thus I- transport function is mostly associated with the thyroid gland. However, in mammals, I- is also concentrated in a number of tissues other than thyroid, such as lactating mammary glands (MG), gastric mucosa, and salivary glands. Concerning its role in lactating MG, it was established that I- secreted into milk is used by the nursing newborn for thyroid hormone biosynthesis. Na+/I- Symporter (NIS) belonging to a family of Na+/glucose transporters is the transporter responsible of I- accumulation in these tissues. Expression of the NIS gene is under control of unrelated hormones and a distinct regulatory control in two different organs, thyroid and lactating MG. Noticeably, unlike non-lactating mammary gland, NIS is functionally expressed in mammary adenocarcinomas of transgenic mice bearing activated Ras (c-Ha-ras) and Neu (c-erbB-2) oncogenes. Recent studies on the relevance of mgNIS expression in human breast cancer point out that NIS can be considered as an important diagnostic marker in breast disease, and it may be possible to establish a radio-iodide based therapeutic protocol against NIS positive breast tumors. On the other hand, very few is known concerning hormonal and transcriptional regulation of NIS in non-thyroidal tissues such as the mammary glands.

The group’s research activity is focused on the identification of ligands, cis-acting elements (i.e., distal control regions, enhancers, silencers) and transcription factors regulating NIS gene expression in lactating mammary gland, and in breast cancer. In these studies various human breast cancer cell lines in culture, as well as tissues taken from small laboratory animals are used. On one hand, in order to identify ligands and hormones that may induce NIS expression in mammary, we are screening a collection of mammary gland cell lines for NIS gene expression after treatments with combinations of various lactogenic and steroid hormones. On the other hand, we are identifying cis-acting transcriptional elements regulating the gene. For identifying such elements, comparisons are carried out at about 300 kb regions including NIS gene in mouse, rat, and human genomes, and conserved sequences in non-exon regions (such as 5′ upstream, intronic, and 3′ downstream regions) are identified. Then, by cell line transfection based luciferase functional assays, a 5′ upstream region with an mammary cell specific enhancer-like activity was identified. In parallel, the chromatin structure of NIS gene loci in rat genome are analyzed in order to identify nucleosome-free sequences. We believe these sequences may reveal candidate regulatory sequences. Therefore, the transcriptional regulatory response activity in such regions are analyzed with functional assay systems. For identifying transcription factors that may interact with analyzed cis-acting regulatory elements, Electromobility Shift Assay based immunological techniques as well as the heterologous yeast one-hybrid screening assays are used.

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