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- Carlsson, Hanna, 1979, et al.
(författare)
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Cluster analysis of S100 gene expression and genes correlating to psoriasin (S100A7) expression at different stages of breast cancer development
- 2005
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Ingår i: Int J Oncol. ; 27:6, s. 1473-81
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Tidskriftsartikel (refereegranskat)abstract
- Gene expression patterns in ductal carcinoma in situ (DCIS) and invasive and metastatic breast tumors have been determined using serial analysis of gene expression (SAGE). The purpose of this approach was to identify biologically and clinically meaningful subgroups of DCIS with a high risk of progression to invasive disease. The analyses have led to the identification of several differentially expressed genes, such as HIN-1, dermcidin and S100A7 (psoriasin). The aim of the present study was further to delineate the expression profile of S100 genes using information from 22 breast epithelial SAGE libraries. We demonstrated the down-regulation of S100A6 and S100A10 in breast cancer, irrespective of pathological stage. S100P and S100Z were both up-regulated in cancer; whereas S100A7, S100A8 and S100A9 were strongly up-regulated only in DCIS. The hierarchical clustering of S100 gene expression in these 22 libraries revealed two major groups with distinguishable S100 gene expression profiles. One of them was characterized by the high concomitant expression of S100A7, S100A8 and S100A9. Using SAGE informatics, we found 21 genes with a high positive correlation to S100A7 expression in libraries representing different categories of tissues archived at SAGE Genie, suggesting a function of psoriasin that is not tissue specific. Like S100A7, several of these genes displayed cation-binding properties. We also report the strong correlation in the breast epithelial SAGE libraries between the expression of S100A7 and genes reported as being up-regulated in DCIS, as well as in the inflammatory skin disorder, psoriasis; including RGS5, UPK1A, TMPRSS3, S100A9, p53, SCCA1, SCCA2 and KRT17.
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- Carlsson, Hanna, 1979, et al.
(författare)
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Psoriasin (S100A7) and calgranulin-B (S100A9) induction is dependent on reactive oxygen species and is downregulated by Bcl-2 and antioxidants
- 2005
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Ingår i: Cancer Biol Ther. ; 4:9, s. 998-1005
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Tidskriftsartikel (refereegranskat)abstract
- S-100 proteins are calcium-binding proteins with important growth regulatory functions. Of these proteins, psoriasin and calgranulin-B have been shown to be highly upregulated in ductal carcinoma in situ (DCIS) of the breast and in psoriasis. The purpose of this study was to further elucidate the functional relevance of the overexpression of these two S-100 proteins in psoriasis and DCIS. We report the induction of both proteins by reactive oxygen species, phorbol ester TPA, and the induction of psoriasin in response to the PI3K inhibitor wortmannin. We also demonstrate that Bcl-2 overexpression represses the induction of psoriasin and calgranulin-B under these different conditions. The same effect was obtained with the antioxidant NAC, which indicates that the suppression of psoriasin and calgranulin-B induction is mediated by the antioxidant function of Bcl-2. Furthermore, we demonstrate that overexpression of a dominant negative IKKbeta also inhibits the induction of psoriasin suggesting that the NFkappaB pathway is involved in the induction of this protein. Also, we found NFkappaB responsive DNA elements in the upstream promoter region of psoriasin. MCF10A cells with a stable retroviral overexpression of psoriasin were significantly more resistant to H2O2-induced cell death than control cells further supporting the hypothesis that these S-100 proteins may play a role in oxidative stress response.
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- Petersson, Stina, 1981
(författare)
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Functional genetic studies of Psoriasin: a potential biomarker for breast cancer with a poor prognosis
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Breast cancer is the most common malignancy in women. There is a high degree of heterogeneity in breast tumours and they can be divided into subtypes that have different expression pattern and clinical outcome. Ductal Carcinoma in situ (DCIS) is regarded as a precursor of invasive ductal breast cancer. Some DCIS lesions will not change in many years, while other will rapidly progress into invasive cancer. It is therefore important to be able to distinguish clinical subgroups of DCIS with a high risk of progression to invasive disease. Aim: Psoriasin is one of the most abundant transcripts in high-grade DCIS with higher risk of local recurrence. Psoriasin has been associated with poor clinical outcome, suggesting its potential involvement in tumour progression. To date, several functions of psoriasin have been proposed, but none of these can fully explain its involvement in breast tumour progression. The aim of this thesis was to elucidate the functional relevance of psoriasin for the initiation and progression of DCIS, and to gain insight into regulatory pathways that control the expression. Results: High-grade DCIS is characterised by a high apoptotic rate and reactive oxidant species (ROS) are known to influence this process. We report the induction of psoriasin by ROS in normal mammary epithelial cells. This induction was repressed by the anti-apoptotic protein Bcl-2 and the antioxidant NAC. Normal mammary epithelial cells with a stable retroviral overexpression of psoriasin were significantly more resistant to ROS-induced cell death. Furthermore, we demonstrate that the NF-κB pathway is potentially involved in the induction of psoriasin expression. (Paper I) IFNγ has been shown to exert anti-tumour action in breast cancer. We report the downregulation of psoriasin by IFNγ in a breast cancer cell line and the downregulation of psoriasin induced by culturing mammary epithelial cells in suspension (loss of contact to extracellular matrix). This effect was shown to be mediated by the activation of the STAT1 signalling pathway. In a mouse mammary epithelial cell line with tetracycline-induced psoriasin expression, we observed the increased viability of psoriasin-expressing cells after IFNγ treatment. (Paper II) The massive induction of psoriasin in suspension culture compared to other stimuli (starvation, confluence and ROS) suggests that changes in adhesion to the extracellular matrix may contribute to the expression of psoriasin. We showed that the downregulation of intercellular adhesion molecule 1 (ICAM-1) (by short hairpin RNA) in mammary epithelial cells increased the expression of psoriasin, through the phospholipase C (PLC)-IP3 pathway, as well as the oncogenic protein mucin1 (MUC1). (Paper III) The interaction between breast epithelial cells and the extracellular matrix contribute to pathological processes and to the normal development of a differentiated structure. Psoriasin has previously been related to epithelial cell differentiation in the skin. We now report that mammary epithelial cells shifted from a CD44+/CD24- to a CD44-/CD24+ phenotype (representing differentiated luminal epithelia) when cultured in confluent and suspension conditions. Interestingly, this result was not observed when psoriasin was suppressed using short hairpin RNA. (Paper IV) Conclusions: We have shown data suggesting that the high expression of psoriasin in high-grade DCIS tumours may be dependent on the production of ROS and a change in adhesion to the ECM, involving ICAM-1 and MUC1. The psoriasin expression leads to increased survival of the breast epithelial cells. Our data also reveal that psoriasin is tightly linked to the expression of CD24. Therefore, it is likely that psoriasin play a role in the differentiation of mammary epithelial cells.
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- Petersson, Stina, 1981, et al.
(författare)
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S100A7 (Psoriasin), highly expressed in ductal carcinoma in situ (DCIS), is regulated by IFN-gamma in mammary epithelial cells.
- 2007
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Ingår i: BMC Cancer. - : BIOMED CENTRAL LTD. ; 7:205
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Tidskriftsartikel (refereegranskat)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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