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Submitted on December 16, 2004
Revised on January 11, 2005
Accepted on January 11, 2005

Downregulation of the tumor suppressor protein 14-3-3sigma is a sporadic event in cancer of the breast

José M. A. Moreira, Gita Ohlsson, Fritz E. Rank, and Julio E. Celis

Proteomics in Cancer, Danish Cancer Society, Copenhagen Ø DK-2100

Corresponding Author: jom{at}cancer.dk

14-3-3 proteins compose a family of highly conserved and broadly expressed multifunctional regulatory proteins that are involved in various cellular processes, such as cell cycle progression, cell growth, differentiation, and apoptosis. Transcriptional expression of the sigma isoform of 14-3-3 is frequently impaired in human cancers including carcinomas of the breast, which has led to the suggestion that this protein might be involved in the neoplastic transformation of breast epithelial cells. Here we report on the analysis of 14-3-3sigma expression in primary breast tumors using a proteomic approach complemented by immunohistochemical analysis by means of specific antibodies against this isoform. We show that the levels of expression of 14-3-3sigma were similar in non-malignant breast epithelial tissue and matched malignant tissue, with only sporadic loss of expression observed in 3 out of the 68 tumors observed. Moreover, we show that 14-3-3sigma immunoreactivity was restricted to epithelial cells, and significantly stronger in the myoepithelial cells that line the mammary ducts and lobules. The lack of expression of 14-3-3sigma in the three breast carcinomas was not associated with high levels of expression of the dominant-negative transcriptional regulator delta Np63 or with increased expression of estrogen-responsive finger protein (Efp), a ubiquitin-protein ligase (E3) that targets 14-3-3sigma for proteolysis. Validation of the results was performed retrospectively on an independent clinical tumor sample set using a tissue microarray containing 65 primary tumors. Our data suggest that contrary to what was previously thought, loss of expression of 14-3-3sigma protein is not a frequent event in breast tumorigenesis.


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