Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 161, Issue 2, Pages 471-480Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/S0002-9440(10)64203-4
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Funding
- NCI NIH HHS [R01 CA064786, R37 CA064786, CA-64786-02] Funding Source: Medline
- PHS HHS [44838] Funding Source: Medline
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Conversion of fibroblasts into myofibroblasts as mediated by transforming growth factor-beta1 (TGF-beta1) is the most prominent stromal reaction to a number of epithelial lesions including breast cancer. To identify genes which are regulated during this process, the mRNA profiles from primary breast fibroblasts treated with or without TGF-beta1 were analyzed by differential display. Ninety-five differentially expressed transcripts were PCR-cloned and sequenced, and 28 clones were selected for verification in a hybridization array. By use of gene-specific sequence tags, nine differentially expressed genes were identified. one of the clones, identified as CLIC4, a member of the CLIC family of chloride channels, was up-regulated more than 16 times in myofibroblasts and was therefore chosen for further analysis. Using RT-PCR, comparison with ClIC1, CKIC2, CLIC3, and CLIC5 demonstrated that CLIC4 was unique by being up-regulated by TGF-beta1 in myofibroblasts. Immunohistochemistry showed a hitherto unknown, distinctive pattern of CLIC4 expression in breast stroma. Whereas normal breast fibroblasts were devoid of CLIC4 protein expression, myofibroblasts of breast carcinomas were strongly CLIC4-positive. The functional significance of CLIC4 was analyzed in MEF/3T3 fibroblasts by conditional expression using the tetracycline-repressive gene regulation system. In a migration assay, we found that CLIC4 inhibited cell motility by 27%. These results suggest that CLIC4 is differentially regulated in fibroblasts and that its expression contributes to a collective stationary myofibroblast phenotype.
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