Altering telomerase to prevent breast cancer progression
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 goal of this proposal is to explore two new strategies for blocking breast cancer progression and tumor maintenance. Both involve altering the action of telomerase in breast cancer cells, but in different ways. These are early experiments designed for the ultimate long-term goal of using these novel strategies clinically, in the prevention and/or treatment of breast cancer.
 
 
 
 
 
 
 
 Several years ago in my laboratory, we discovered the enzyme telomerase, which is the enzyme responsible for creating the DNA which makes up telomeres. Telomeres consist of DNA sequences, repeated over and over at the ends of chromosomes, which bind protein factors and make a "cap" securing the end of every chromosome, preventing it from fraying away. The telomerase enzyme adds short stretches of DNA to the ends (the telomeres) of all chromosomes as cells are dividing. This extra DNA makes up for the loss of DNA from each chromosomal end that is incurred by the natural inability of chromosomal DNA replication to replicate the chromosomal ends. Without replenishments by telomerase, as cells repeatedly divide, the telomeres gradually shrink. When telomeres become too short, cells stop dividing. Thus, for a cell to keep dividing, telomerase is needed in sufficient amounts to keep the chromosomes "topped up". Cancer cells, which divide much more than many normal cells in the body, often activate telomerase. This is thought to contribute to their ability to keep dividing.
 
 
 
 
 
 
 
 We have discovered that telomerase is active in breast cancer cell lines grown in the laboratory. Therefore, we have decided to alter the action of telomerase in breast cancer cells in two very different ways, both designed to stop these tumor cells from dividing. 
 
 
 
 
 
 
 
 In the first strategy, inhibitors of telomerase will be used to prevent telomerase from maintaining telomeres. We have made the novel finding that some of the same kinds of drugs that stop the HIV-1 virus from replicating can also inhibit human telomerase, and cause telomere shortening in at least some types of human cells grown in the laboratory. Therefore, the first goal of this proposal is to test whether we can shorten telomeres in human breast cancer cells, using breast cancer cells explanted directly from patient biopsies into short-term primary cultures in the laboratory. Based on previous results with simple organisms, we predict that without telomerase working properly, the telomeres will run down until the cells stop dividing. In this way, we will find out about the role of telomerase in breast cancer progression and tumor maintenance. The ultimate long-term goal is to determine whether telomerase inhibitors will be useful in the prevention and/or treatment of breast cancer.
 
 
 
 
 
 
 
 The second strategy, rather than seeking to shut off telomerase action as the first strategy does, instead actually turns the action of an active telomerase against the breast cancer cells. This active telomerase is one we will have engineered to direct the synthesis of what we term "toxic" telomeric DNA sequences in breast cancer cells. When we do this in simpler organisms, they very quickly cease dividing because of these adverse telomeric sequences.
 
 
 
 
 
 
 
 The planned research explores new strategies for potential treatment of breast cancer and will be greatly augmented by the multidisciplinary approach involving the combined expertise of this laboratory on telomeres and telomerases with those of Dr. Shanaz Dairkee in breast cancer cell explants and cell biology, and Dr. Robert Debs in gene transfer methods.