Maspin: Breast Cancer Suppression through Enzyme Inhibition?
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: In 1994 a class II tumor suppressor gene called maspin was identified from patients with breast cancer. Although a decade of research on maspin has solidified its function as an anti-tumor protein, there are conflicting interpretations of the findings, and differing opinions about maspin's mechanism of action. Opinions differ on maspin's site of action (from the inside of the cell vs. the outside), on its biochemical activity (protease inhibitor vs. cell surface ligand), and even on its effects on tumors (tumor suppressor vs. metastatic gatekeeper). Here we seek to clarify maspin's mechanism of action. Our work on maspin has led us to another protein called the proteasome. The proteasome is found inside cells where it acts as a machine to degrade proteins. This process is a normal function in cells, as they must turnover older proteins. Recently though, the proteasome has been implicated in cancer. Our work connects these two seemingly unrelated regulators of tumor progression. 
 
 
 
 
 
 
 
 Our preliminary results show that maspin has very little impact on gene expression, but that is has widespread effects on protein expression. This is an unusual observation, but one that would be expected if maspin regulates the proteasome. Based on these results, we suggest that maspin's anti-metastatic activity results from its ability to regulate protein degradation by the proteasome. To test this hypothesis we propose to: 1) Measure the ability of maspin to directly inhibit protease activity of the proteasome in purified systems and in cells, and 2) Measure the effects of maspin on the compliment of proteins in cells that are marked for proteasome degradation by molecular tags. 
 
 
 
 
 
 
 
 One aspect of our study will make use of standard approaches in protein and cellular biochemistry. We will use these techniques to measure the direct effects of purified maspin on proteasome function, and to measure the effects of maspin on the proteasome in breast cancer cells. A separate aspect of the study will involve a highly sophisticated and innovative strategy toward surveying the effects of maspin on the cellular process that tags proteins for degradation by the proteasome. This tagging is called ubiquitination and we plan to study it with a technique called proteomics. Proteomics allows one to measure the effects of a chemical modification (like tagging with ubiquitin) on thousands of proteins at once. This methodology has not been used extensively in breast cancer research.
 
 
 
 
 
 
 
 The proposal is innovate for three reasons: 1) the hypothesis is entirely novel and untested. It connects two seemingly unrelated proteins, maspin and the proteasome, 2) one of the approaches we plan to use to study the effects of maspin is called proteomics. This highly sophisticated and technical strategy allows one to measure small changes to protein structure, like their tagging for degradation. The approach makes use of mass spectrometry to assess changes across the entire complement of cellular proteins in one experiment. The power of proteomic analysis has not been widely applied to gain insight into breast cancer, 3) the results of the study are likely to suggest highly innovative avenues for drug design in breast cancer. If maspin suppresses breast cancer by acting on the proteasome, then this molecular target would become a new and validated target for therapeutic intervention in breast cancer.