Activity Based Profiling of Breast Cancer Xenografts
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: The molecular features special to metastatic breast carcinomas that support their motile and invasive behavior are complex and ill-defined. It is thought that extracellular enzymes, called proteases, play a central role in promoting their aggressive properties. However, studies that measure the abundance of cancer-associated proteases may not provide of clear picture of their function. For example, the coincidental or coordinated upregulation of both a protease and its endogenous inhibitor (as occurs in breast cancer for uPA and its inhibitor PAI-1) might result in little net difference in enzyme activity, thus producing a protease whose quantity, rather than catalytic power, changes during tumorigenesis. 
 
 
 
 
 
 
 
 Conventional genomics (DNA/RNA-based) and proteomics (protein/peptide-based) methods measure changes in transcript and protein abundance, respectively, and therefore provide only an indirect assessment of protein function. In our research group, we are addressing the need for higher-order functional proteomics technologies by developing and applying chemical probes that measure protein activity rather than abundance. We refer to this method as "activity-based protein profiling" (ABPP). 
 
 
 
 
 
 
 
 Our laboratory’s initial research efforts, supported by previous CBCRP awards to Dr. Cravatt, allowed us to successfully apply ABPP probes to the proteomic analysis of several enzyme classes across a panel of human breast cancer cell lines. These studies resulted in the identification of multiple enzyme activities, including several serine hydrolases that were differentially expressed in estrogen receptor (ER)-positive and ER-negative breast cancer lines. A critical next step in validating the association of these enzymes with breast cancer is to demonstrate that their expression pattern is maintained in human tumors grown in animal models (i.e., xenografts). Taking advantage of the mixed species nature of these breast cancer xenograft models, we will also attempt to distinguish tumor enzyme activities that are expressed by cancer cells (human) and by infiltrating stroma (mouse). Next, we also plan to determine the enzyme activity profiles of circulating tumor cells. Finally, we will determine the enzyme activity profiles of metastasized variants of human breast cancer lines and compare these profiles to those of the parent lines. 
 
 
 
 
 
 
 
 Progress towards better diagnostic and therapeutic agents to treat breast cancer relies heavily on the ability to identify new proteins that are both: (1) upregulated in breast cancer samples, and (2) of functional relevance to the progression of this disease. We anticipate that our chemical proteomics studies will identify novel key enzymes that support the growth and metastatic properties of breast cancer in vivo. These enzymes will in turn represent valuable markers and targets for future studies aimed at understanding, diagnosing, and ultimately treating breast cancer.