The Importance of Growth Inhibitory Signals in Normal Breast
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 diagnosis of breast cancer is a common and terrifying occurrence that elicits justified fear not only of the disease itself but also of the often grueling and toxic treatment regiments. Recently, however, there have been positive developments in the area of breast cancer research that have been translated into a promising new therapy for some patients. This research centers on a particular protein, HER-2, that is vastly overabundant in about 30% of breast cancers. The newly FDA approved therapy that targets HER-2 and the cancerous cells that harbor it on their surface, is called Herceptin. It is the first successful breast cancer treatment that targets a distinct genetic alteration as opposed to traditional approaches aimed essentially at all rapidly dividing cells, including normal healthy ones As such, the development of Herceptin has led the way into a new era of targeted cancer therapies. It has proven the principle that if researchers can identify specific molecular alterations that are unique to cancer cells, effective therapies can be developed.
 
 
 
 
 
 
 
 Despite the success of Herceptin and intense investigation by our lab and others, much remains to be learned about the precise mechanism by which overabundant HER-2 leads to the development/progression of breast cancer. A more complete understanding of the events triggered by HER-2 will be required to understand why some patient's tumors do not respond to Herceptin and for the development of improved, "second generation" therapies directed at HER-2. The primary goal of this study is to the test the hypothesis that naturally occurring, growth inhibitory signals present in the normal breast tissue constitute the critical, first-line, defense mechanism against breast cancer and that HER-2 is tumor promoting because it antagonizes these inhibitors.
 
 
 
 
 
 
 
 In order to the study the interaction between growth inhibitory signals and HER-2, we will use a cell culture assay where normal breast cells form tiny ductal structures in 3-dimensional gels made from a complex mixture of proteins that normally surrounds these cells in the human breast. Using this system, we can experimentally manipulate the concentration and activity of particular growth inhibitors to determine if the are critical for maintaining the size, shape and normal architecture of these mini breast duct structures. Once we establish the importance of a particular factor, we will test the ability of HER-2 to counter its function. We can test the influence of HER-2 in this system because we have engineered breast cells that can easily be manipulated (by the addition of an antibiotic, tetracycline) to turn on and off the HER-2 protein.
 
 
 
 
 
 
 
 This study combines the knowledge obtained from cutting-edge DNA chip technologies with a culture assay that models normal breast structures. This potential powerful combination allows us to form a hypothesis based on a large number of gene changes associated with HER-2 overabundance and then test its functional importance in the context of breast structures. A second innovative aspect of this work is its focus on the interaction between HER-2 and growth inhibitory pathways. HER-2 is growth factor receptor and as such has mostly been studied in terms of its ability to cause cells to rapidly grow and divide. However, the idea that a major way that HER-2 accomplishes this is by antagonizing naturally occurring growth inhibitors has not been vigorously tested.