Telomerase, mammary stem cells and breast cancer
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: Telomerase has been proposed as a key to cellular immortality, a so-called "fountain of youth". In both cancer and normal stem cells the presence of telomerase allows them to divide repeatedly. Telomerase is “turned on” in 90% of human breast cancers and DCIS, making its re-activation one of the most common changes in the disease. One function of telomerase in stem/progenitor cells is to counter telomere (i.e., the ends of chromosomes) shortening with each cell division. In the absence of telomerase, the ultimate capacity of human cells to replicate is limited to 50-100 divisions, which is thought to be the basis for human aging due to cell and tissue senescence. 
 
 
 
 
 
 
 
 During the IDEA funding from the CBCRP prior to this renewal we were able to achieve a number of milestones to lay the groundwork for this project. We have been able to generate a mouse model where the protein component of telomerase, TERT, is expressed in a mammary-dependent manner. These mice will develop cellular hyperplasia resembling early stage breast cancer, and the mammary glands show an increase in stem/progenitor cells when TERT is activated. Finally, we have developed evidence that the effects of TERT on restoring chromosome ends may be separable from its ability to activate stem/progenitor cells in a mammary-specific manner. Thus, this recent data from my laboratory challenges this conventional TERT-telomerase paradigm by showing a novel function outside of chromosome end repair. In this project, we will directly test the hypothesis that “conditional activation” of TERT in adult mouse mammary epithelium leads to hyperproliferation and breast cancer by promoting expansion of mammary stem/progenitor cells. We will also use genetic means to determine definitively if these effects of TERT involve telomere synthesis. Furthermore, we will study TERT's more established role in telomere maintenance to determine if telomere dysfunction impairs mammary stem cell function. To test these hypotheses, we have genetically engineered mice that enable us to switch the telomerase enzyme “on” by feeding the mice a harmless antibiotic. This will enable us to determine if telomerase can cause normal breast epithelial cells to divide, if breast stem cells are now more active, and if telomerase can cause development of breast cancer. Because we can control the expression of telomerase in the breast by feeding the mouse the antibiotic, we can also take the antibiotic away and ask if breast cancers that arise still require expression of the telomerase enzyme.
 
 
 
 
 
 
 
 We hope to develop a useful pre-clinical model to determine whether inhibiting telomerase can be a useful therapeutic approach for breast cancer. Much of the suffering associated with breast cancer occurs because of relapse of metastatic disease, which is becoming increasing associated with the presence of stem cells that underlie the development, progression, resistance to treatment, and tumor recurrence processes. Therefore, understanding the molecular details of stem cell biology in the context of the mammary gland and breast cancer will be crucial to developing effective therapeutics to ultimately reduce the burden the disease.