The Expression of Psoriasin (S100A7) and CD24 Is Linked and Related to the Differentiation of Mammary Epithelial Cells

Psoriasin (S100A7), a member of the S100 family of calcium-binding proteins, is highly expressed in high-grade ductal carcinoma in situ (DCIS) and in the benign hyperproliferative skin disorder psoriasis. The gene that encodes psoriasin and many other S100 genes are located within a gene cluster on chromosome region 1q21, known as the epidermal differentiation complex. This cluster contains genes for several differentiation markers that play important roles in the terminal differentiation of the epidermis. The purpose of the present study was to evaluate the role of psoriasin in the differentiation process of mammary epithelial cells. Normal mammary epithelial cells (MCF10A) cultured in confluence and suspension, conditions known to induce psoriasin expression, demonstrated a shift towards a more differentiated phenotype indicated by an increase in the expression of the luminal differentiation markers CD24 and MUC1 and the reduced expression of the breast stem cell marker CD44. The expression of psoriasin and MUC1 was most pronounced in the CD24$^+$-enriched fraction of confluent MCF10A cells. The shift towards a more differentiated phenotype was abolished upon the downregulation of psoriasin using short hairpin RNA (shRNA) and small interfering RNA (siRNA). Using specific inhibitors, we showed that psoriasin and CD24 expression was regulated by reactive oxygen species (ROS) and the nuclear factor (NF)-κB signaling pathways. While immunohistochemical analyses of DCIS showed heterogeneity, the expression of psoriasin and CD24 showed a similar staining pattern. Our findings suggest that the expression of psoriasin is linked to the luminal differentiation marker CD24 in mammary epithelial cells. Psoriasin demonstrated an essential role in the shift towards a more differentiated CD24$^+$ phenotype, supporting the hypothesis that psoriasin plays a role in the differentiation of luminal mammary epithelial cells

S100A7 (Psoriasin), highly expressed in Ductal Carcinoma In Situ (DCIS), is regulated by IFN-gamma in mammary epithelial cells

<p>Abstract</p> <p>Background</p> <p>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 <it>in situ </it>(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.</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>Conclusion</p> <p>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.</p

Functional genetic studies of Psoriasin: a potential biomarker for breast cancer with a poor prognosis

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

Patients experience of side effects associated with chemotherapy - a litterature review

Bakgrund: I Sverige diagnostiseras varje år ungefär 55 000 människor med cancer och risken att få en cancersjukdom någon gång i livet är cirka 30 procent. En vanlig behandlingsmetod för att bli av med cancer är cytostatikabehandling men behandlingen kan ge en rad olika biverkningar såsom exempelvis håravfall, illamående och trötthet. Syfte: Syftet med arbetet var att undersöka hur illamående, trötthet och håravfall i samband med cytostatikabehandling påverkar patientens dagliga liv. Metod: En litteraturstudie utarbetades och till grund för studien valdes elva vetenskapliga artiklar genom systematisk sökning i relevanta databaser. Dessa analyserades och användes i sammanställningen av arbetets resultat. Resultat: Patienter som får cytostatikabehandling upplevde ofta biverkningarna i samband med behandlingen som påfrestande och traumatiska. Håravfall, alopecia, var den biverkning som de flesta patienter upplevde som jobbigast relaterat till att de kände sig sjukare och att sjukdomen blev mer synlig för omgivningen. Slutsats: Biverkningar i samband med cytostatikabehandling kan påverka patientens dagliga liv på ett negativt sätt till exempel genom att de isolerar sig från sin omgivning

Continuospel på barockcello : en diskussion kring Quantz’ idéer och en undersökning av mina egna musikaliska verktyg

Konsertprogram: JS Bach, Sonat för Flöjt och Basso continuo, BWV 1034.Medverkande: Kristine West, blockflöjt, Marcus Mohlin, cembalo, Stina Petersson, barockcello</p

Produktvalsprincipen efter REACH

Validerat; 20101217 (root