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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online April 27, 2005 as doi:10.1096/fj.04-2970fje. |
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,1,2
* Department of Molecular and Experimental Medicine,
Department of Molecular Biology and
Department of Cell Biology, The Scripps Research Institute, La Jolla, California, USA; and
The Cancer Research Center, Program on Cell Adhesion at The Burnham Institute, La Jolla, California, USA
1 Correspondence: Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037, USA. E-mail: emilyc{at}scripps.edu
SPECIFIC AIMS
The aims of this study were: 1) to apply a sophisticated shot-gun proteomic method (MudPIT) to carry out the proteome analysis of breast cancer cells with or without the metastatic tumor suppressor gene maspin; and 2) to generate a mechanistic hypothesis of maspin’s role in tumor metastasis based on the observed proteome modification.
PRINCIPAL FINDINGS
1. A large scale proteome analysis of metastatic breast cancer cells and of the changes that took place by restoring maspin expression was conducted
2. Three metastasis-related protein networks affected by maspin were identified: actin filaments, apoptosis, and protein degradation
3. A new observation was uncovered: change of the proteasome activity occurred in maspin-expressing breast cancer cells
4. The observed connection between maspin and the proteasome provided an alternative mechanistic hypothesis of how maspin functions as a metastatic suppressor gene
CONCLUSIONS AND SIGNIFICANCE
Tumor metastasis suppressor genes have been studied extensively for their importance in understanding the regulation of cancer metastasis. However, the mechanism of most of these tumor metastasis suppressor genes remains uncertain. In our study, we used proteome changes as a molecular description and as a measure of the phenotypic changes caused by expressing a metastatic suppressor gene, maspin, in breast cancer cells. Based on the protein-profiling findings, we found new mechanistic insights regarding maspin’s function, and provided an illustration for examining metastatic suppressor genes by a proteomic approach.
The mechanisms by which maspin elicits its antitumor and anti-metastatic effects are still the subject of intense study. Nevertheless, maspin appears to be multifunctional and exists in several cellular locations. Although the primary effect of maspin on tumor phenotype seems to be anti-metastasis, it has been found to have a reduction in invasion capacity, an inhibition in angiogenesis, and have a similar function in other cancers. To gain insight into the molecular mechanisms of maspin’s tumor suppressor function, we assessed the nature and scope of maspin’s effects on the carcinoma proteome. This was done through shotgun proteomics, using multidimensional protein identification technology (MudPIT), which couples tandem mass spectrometry with multiple liquid chromatography steps.
We identified the potential molecular pathways corresponding to the observed phenotypic changes in maspin-transfected breast cancer cells. We also revealed a novel observation between the proteasome and maspin: an inverse correlation between maspin and 20S proteasome activity. Dysregulation in the expression of 20S proteasome subunits seemed to accompany the decreased cellular proteasome activity in the maspin-transfected breast cancer cells. This novel observation provides an alternative mechanistic hypothesis of how maspin functions as a metastatic suppressor gene and can be used to address the multifaceted function and cellular distribution of maspin protein.
As we continue to learn about the aberrant regulation of the ubiquitin-proteasome pathway in cancer cells and the resulting changes in its housekeeping functions, we can speculate that alteration in proteasome activity might be a key step toward metastasis. Based on the present study, we speculate that many of the effects that have been associated with maspin could be attributed to maspin’s function in maintaining the delicate and specific regulation of the ubiquitin-proteasome pathway, the net result of which could influence metastasis-related events. Although we have only a few clues about the details of the mechanism by which maspin can modulate proteasome activity directly or indirectly, our data point toward a new hypothesis of the molecular mechanism of maspin, and suggest a potential contribution of the ubiquitin-proteasome pathway in the regulation of tumor metastasis.
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FOOTNOTES
2 Current address: Stowers Institute for Medical Research, Kansas City, MO 64110, USA. 
To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.04-2970fje; doi: 10.1096/fj.04-2970fje
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