Expression of Cyclophilin B is Associated with Malignant Progression and Regulation of Genes Implicated in the Pathogenesis of Breast Cancer

• DOI: 10.2353/ajpath.2009.080753
• Publication Date: 2008-12-05T01:46:02Z
• Authors: Feng Fang; Ayanna J. Flegler; Pan Du; Simon Lin; Charles V. Clevenger
• Keywords: 0303 health sciences; Reverse Transcriptase Polymerase Chain Reaction; Gene Expression Profiling; Blotting, Western; Fluorescent Antibody Technique; Breast Neoplasms; Immunohistochemistry; 3. Good health; Gene Expression Regulation, Neoplastic; Cyclophilins; 03 medical and health sciences; Tissue Array Analysis; Cell Line, Tumor; Disease Progression; Humans; Female; Neoplasm Invasiveness; Cell Proliferation

Cyclophilin B (CypB) is a 21-kDa protein with peptidyl-prolyl cis-trans isomerase activity that functions as a transcriptional inducer for Stat5 and as a ligand for CD147. To better understand the global function of CypB in breast cancer, T47D cells with a small interfering RNA-mediated knockdown of CypB were generated. Subsequent expression profiling analysis showed that 663 transcripts were regulated by CypB knockdown, and that many of these gene products contributed to cell proliferation, cell motility, and tumorigenesis. Real-time PCR confirmed that STMN3, S100A4, S100A6, c-Myb, estrogen receptor alpha, growth hormone receptor, and progesterone receptor were all down-regulated in si-CypB cells. A linkage analysis of these array data to protein networks resulted in the identification of 27 different protein networks that were impacted by CypB knockdown. Functional assays demonstrated that CypB knockdown also decreased cell growth, proliferation, and motility. Immunohistochemical and immunofluorescent analyses of a matched breast cancer progression tissue microarray that was labeled with an anti-CypB antibody demonstrated a highly significant increase in CypB protein levels as a function of breast cancer progression. Taken together, these results suggest that the enhanced expression of CypB in malignant breast epithelium may contribute to the pathogenesis of this disease through its regulation of the expression of hormone receptors and gene products that are involved in cell proliferation and motility.