Abstract | BACKGROUND: The aim of the present work was to explore signal transduction pathways used in the regulation of S100A7 ( psoriasin). Members of the S100 gene family participate in many important cellular functions. Psoriasin, S100A8 ( calgranulin A) and S100A9 ( calgranulin B) are expressed in ductal carcinoma in situ ( DCIS), as well as in the hyperproliferative skin disease, psoriasis. In the latter condition, a disturbance in the STAT pathway has recently been reported. This pathway is implicated in the regulation of IFN-gamma, widely recognized as a key cytokine in psoriasis. IFN-gamma also exerts anti- tumor action in a number of tumor cell types, including breast cancer. We therefore examined the effect of IFN-gamma and STAT-signaling on the psoriasin expression. METHODS: We established a TAC2 mouse mammary epithelial cell line with tetracycline-inducible psoriasin expression (Tet-Off). Viability in cell culture was estimated using MTS assay. Protein and gene expression were evaluated by Western blotting and quantitative real-time PCR. Statistical analyses were assessed using a one-tailed, paired t-test. RESULTS: We report the downregulation of psoriasin by IFN-gamma in the MDA-MB-468 breast cancer cell line, as well as the downregulation of psoriasin induced by anoikis in cell lines derived from different epithelial tissues. In contrast, IFN-gamma had no suppressive effect on calgranulin A or calgranulin B. IFN-gamma is an important activator of the STAT1 pathway and we confirmed an active signaling pathway in the cell lines that responded to IFN-gamma treatment. In contrast, in the SUM190 breast carcinoma cell line, IFN-gamma did not suppress the expression of endogenous psoriasin. Moreover, a reduced phosphorylation of the STAT1 protein was observed. We showed that IFN-gamma treatment and the inhibition of the transcription factor NFkappaB had a synergistic effect on psoriasin levels. Finally, in TAC2 cells with tetracycline-induced psoriasin expression, we observed the increased viability of psoriasin-expressing cells after IFN-gamma treatment. CONCLUSION: Our data support the possibility that psoriasin expression is transcriptionally suppressed by IFN-gamma and that this effect is likely to be mediated by the activation of the STAT1 signaling pathway. The increased viability of psoriasin-expressing cells after IFN-gamma exposure suggests that psoriasin expression leads to the development of an apoptosis-resistant phenotype.
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Authors | Stina Petersson, Anna Bylander, Maria Yhr, Charlotta Enerbäck |
Journal | BMC cancer
(BMC Cancer)
Vol. 7
Pg. 205
(Nov 06 2007)
ISSN: 1471-2407 [Electronic] England |
PMID | 17986321
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Calcium-Binding Proteins
- Calgranulin A
- Calgranulin B
- NF-kappa B
- S100 Calcium Binding Protein A7
- S100 Proteins
- S100A7 protein, human
- STAT1 Transcription Factor
- STAT1 protein, human
- Interferon-gamma
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Topics |
- Animals
- Apoptosis
- Breast
(metabolism)
- Breast Neoplasms
(metabolism)
- Calcium-Binding Proteins
(biosynthesis)
- Calgranulin A
(biosynthesis)
- Calgranulin B
(biosynthesis)
- Cell Line, Tumor
- Cell Survival
- Cells, Cultured
- Epithelium
(metabolism)
- Gene Expression Regulation
- Interferon-gamma
(metabolism)
- Mice
- Models, Biological
- NF-kappa B
(metabolism)
- Phenotype
- S100 Calcium Binding Protein A7
- S100 Proteins
- STAT1 Transcription Factor
(metabolism)
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