Immortalization of Human Mammary Epithelial Cells by ZNF217
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 ways in which individual cells age, control their capacity to divide, and escape these limitations to form breast cancer are the central themes of our research. After a limited number of cell divisions (generally 50-100), normal human breast cells are no longer capable of further proliferation. Scientists now believe that this limited lifespan, referred to as ‘replicative senescence’, arose as a cancer prevention mechanism in long-lived organisms, such as humans. Development of most adult onset cancers requires multiple DNA/chromosomal changes that accumulate with successive cell divisions. The limited cell division capacity of normal cells makes it highly unlikely that they could accumulate so many genetic errors. Thus, to overcome this natural barrier most human breast cancers have developed ways to overcome replicative senescence. One common mechanism is to make a protein complex called telomerase which repairs the ends of chromosomes that otherwise shorten with each cell division. Another cancer-promoting property is lack of stability of the DNA genome, called genomic instability, which allows more DNA/chromosomal errors to arise with each cell division. 
 
 
 
 
 
 
 
 Our laboratory has pioneered the development and use of cultured human mammary epithelial cells (HMEC) in order to gain information on defects in growth control processes that occur during breast cancer progression. We have been able to convert normal lifespan HMEC into immortal cells by using chemical carcinogens. However, we still do not know the specific genetic and molecular changes that underlie this process. Recent studies in our laboratory have identified a potential breast cancer-promoting gene (i.e., oncogene). This gene, called ZNF217, is present at higher than normal levels in many breast tumor cells. When we cause ZNF217 to become increased in normal HMEC, then they continue dividing past the point of replicative senescence. We believe that ZNF217 can influence the production of telomerase. Using the BCRP funding we plan a more detailed confirmation of these observations, and to perform additional studies on the direct function of ZNF217 in HMEC and breast cancer cells. These experiments include looking at the effect of ZNF217 on common tumor suppressors (i.e., p53), growth control processes, genomic instability, and the internal skeleton of cells. In addition, we will characterize the genes that are regulated by this potential transcription factor. 
 
 
 
 
 
 
 
 By studying this breast cancer associated oncogene, we should gain new information on the pathways involved in breast cancer progression, and possibly provide new targets for therapeutic intervention. Thus, we hope to learn which critical step in breast cancer progression is most affected by ZNF217. We predict that if this gene is involved in the earliest phases, then we can explore novel ways of preventing the disease.