Understanding Telomere Dynamics in the 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: Telomeres are the DNA sequences on the ends of all our chromosomes that cap and protect them from breaking down and joining with other chromosomes. Telomeres are made by a special enzyme system called telomerase, which is present in very few cells in the body, such as stem cells, but is not found in most normal human cells. Because most human cells lack telomerase, telomeres shorten in many of our organs as we age and this can limit their ability to regenerate. Cancer cells learn to reactivate telomerase, an important step in allowing cancer cells to divide indefinitely. We have shown that telomere shortening not only can limit cell division, but can also enhance breast cancer rates by causing chromosomes to break down. How the breast cells respond to this breakdown depends on whether they have lost the p53 tumor suppressor gene.
 
 
 
 
 
 
 
 We hypothesize that breast cancer can be caused by a two step process that involve our telomeres. First, telomeres shorten and chromosomes break down. The body protects itself from these cells by activating p53 and killing them. However, some cells may escape by losing p53 and this chromosomal breakdown begins to cause early breast cancers to form. These early breast cancers cannot grow very large because their short telomeres and broken chromosomes will not allow it. Eventually, cancers can learn to reactivate telomerase which heals the telomeres, stabilizes the chromosomes and allows further growth and spread of the cancer.
 
 
 
 
 
 
 
 We wish to understand how normal breast cells in the mammary gland react to telomere shortening so that we can better understand how this occurs in humans. We will use the mouse as a model system to study this two step process in cancer formation. We are creating mice in which telomerase is off, as in humans, and telomere shorten with aging. If early breast cancers form we will be able to activate telomerase in the mammary glands by feeding the mice a drug that activates the telomerase gene. We will analyze the mammary gland using standard techniques including microscopic analysis, and studies which measure death and proliferation. We will also use exciting new technologies that enable us to carefully examine chromosomes.
 
 
 
 
 
 
 
 Understanding how the mouse mammary gland responds to telomere shortening will enable us to begin to understand how this influences changes in the breasts of women as women age and cancer becomes more common. Our approach of creating a system in which we can study both telomere shortening and telomerase reactivation in a living organism is one that has not yet been achieved and one that will allow us to model the complex changes in human telomeres that occur during human breast cancer. We hope that findings from this study will enable us to better understand how human breast cancer evolves so that we can detect it earlier, treat it more effectively and eventually prevent it from occurring.