Loss of ICAM-1 signaling induces psoriasin (S100A7) and MUC1 in mammary epithelial cells.
Psoriasin (S100A7), a member of the S100 gene family, is highly expressed in high-grade comedo ductal carcinoma in situ (DCIS), with a higher risk of local recurrence. Psoriasin is, therefore, a potential biomarker for DCIS with a poor prognosis. High-grade DCIS is characterized by a high proliferation rate and crowded cells, consequently, lose contact with the extracellular matrix. The aim of this study was, therefore, to elucidate the involvement of adhesion signals in the regulation of psoriasin. Protein expression was evaluated by Western blotting, flow cytometry, and immunohistochemistry, and using breast carcinoma SAGE databases available from the CGAP website. Intercellular adhesion molecule 1 (ICAM-1) was down-regulated in MCF10A cells using short hairpin RNA. We found a significant negative correlation between the expression of ICAM-1 and psoriasin, and a positive correlation between psoriasin and MUC1 in normal and DCIS SAGE libraries. In a cluster analysis of 34 adhesion molecules and 20 S100 proteins, we showed that SAGE libraries expressing the S100 proteins-psoriasin, calgranulin-A, and calgranulin-B-clustered together. Interestingly, the expression of all the three proteins correlated strongly to the oncogenic MUC1. We confirmed the negative correlation between ICAM-1 and psoriasin/MUC1, when normal and breast cancer cells were cultured in suspension and on collagen, respectively. The down-regulation of ICAM-1 by short hairpin RNA in MCF10A cells led to the induction of psoriasin, calgranulin-A, calgranulin-B, and MUC1, and we demonstrated that these up-regulations were not ROS dependent. By blocking the phospholipase C (PLC)-IP3 pathway in these cells, we showed that the induction of psoriasin diminished. The results suggest that psoriasin is an intracellular calcium-dependent target of the PLC pathway. Our findings suggest that the down-regulation of ICAM-1 in mammary epithelial cells may contribute both to the high expression of psoriasin seen in some high-grade DCIS tumors and to the induction of MUC1.
Petersson
S
S
Department of Clinical Genetics, Sahlgrenska University Hospital, SE-413 45 Gothenburg, Sweden. stina.petersson@clingen.gu.se
Shubbar
E
E
Yhr
M
M
Kovacs
A
A
Enerbäck
C
C
D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D040501:Calgranulin A / Q000378:metabolism; D040502:Calgranulin B / Q000378:metabolism; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D003094:Collagen / Q000378:metabolism; D030541:Databases, Genetic; D015536:Down-Regulation; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D042361:Mammary Glands, Human / Q000378:metabolism* / Q000473:pathology; D018396:Mucin-1 / Q000235:genetics / Q000378:metabolism*; D009842:Oligopeptides / Q000138:chemical synthesis / Q000378:metabolism; D034622:RNA Interference; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D010738:Type C Phospholipases / Q000378:metabolism; D015854:Up-Regulation
D040501:Calgranulin A; D040502:Calgranulin B; C060192:MUC1 protein, human; D018396:Mucin-1; D009842:Oligopeptides; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins; C089242:S100A7 protein, human; D018799:Intercellular Adhesion Molecule-1; C047981:arginyl-glycyl-aspartic acid; D015544:Inositol 1,4,5-Trisphosphate; D003094:Collagen; D010738:Type C Phospholipases