Abstract
14-3-3 proteins comprise 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 of the 68 tumors examined. 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 DeltaNp63 or with increased expression of estrogen-responsive finger protein, 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.
Highlights
14-3-3 proteins comprise 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
Immunohistochemical Demonstration of the Presence of 14-3-3 Protein in Normal and Cancerous Breast Tissue—To study changes in 14-3-3 expression that might take place during the progression from normal breast epithelium to invasive breast cancer, we analyzed “normal” tissue and malignant tissue obtained from the same patient by immunohistochemistry
To validate retrospectively in an independent set of specimens the results obtained with the 65 tumor specimens included in our pilot study, we examined the expression of 14-3-3 in a further 65 breast tumor specimens present on the T-BO-1 Tissue Array Research Program (TARP) tissue microarray (TMA)
Summary
14-3-3 proteins comprise 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 isoform of 143-3 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. In primary human epidermal keratinocytes down-regulation of 14-3-3 results in evasion from senescence [13] Overall these lines of evidence suggest that functional inactivation of 14-3-3 may be linked to carcinogenesis, a hypothesis that is supported by the discovery of 14-3-3 downregulation in various human malignancies, including cancer of the breast, stomach, colon, lung, liver, prostate, oral cavity, and vulva (7, 8, 14 –19), attributed to hypermethylation of the CpG island present in the promoter area of the gene. Abrogation of Protein 14-3-3 in Breast Cancer Is Sporadic lung [20], head and neck [21], gastric [22], and pancreatic cancer [23,24,25] suggesting that this protein might play a key role in carcinogenesis through multiple mechanisms
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