Telomerase, Mammary Stem Cells, and Breast Cancer

Institution: Stanford University
Investigator(s): Steven Artandi, M.D., Ph.D. -
Award Cycle: 2007 (Cycle 13) Grant #: 13NB-0179 Award: $360,277
Award Type: IDEA Competitive Renewal
Research Priorities
Biology of the Breast Cell>Biology of the Normal Breast: the starting point

Initial Award Abstract (2007)

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.

Final Report (2009)

Telomeres represent the physical caps that protect the ends of chromosomes and telomerase is an enzyme complex that renews telomeres by adding DNA repeats to chromosome ends. Telomeres and telomerase play crucial roles in breast cancer. As we age, telomeres gradually shorten in our cells. In breast cancer, telomere shortening facilitates rearrangements in our chromosomes that allow for key cancer genes to become abnormal, which contributes to the development of breast cancer. In addition, we have found that the telomerase enzyme has other activities that may stimulate tissue stem cells. We hypothesize that these other activities of telomerase are important for breast cancer development.

We have been intensely investigating new functions for telomerase in stem cell biology and we have made a fundamental, new discovery in this regard, with strong relevance to our Aim 1, which was to understand how telomerase modulates mammary stem cell function. We have found that telomerase actually serves as a cofactor in the Wnt pathway, one of the most important circuits in cancers and stem cells. The telomerase protein component, TERT, interacts with a chromatin remodeling protein, Brg-1, and acts as a co-factor to activate subsets of genes controlled by Wnts, which are soluble growth factors secreted in tissues. This role for TERT is independent of its function in adding telomere repeats. We find that TERT interacts with Brg-1 and beta-catenin at specific chromatin sites in Wnt target genes in vivo. These results were recently published in Nature. Wnt signaling has already been established as an important pathway in mammary gland development and in breast cancer. Thus, we have found that two pathways important in breast cancer - Wnts and telomerase – are intimately linked.

We have also made excellent progress in understanding how telomere shortening impairs mammary tissue function. We have shown that with critical telomere shortening, mammary stem cell self-renewal is impaired. This also results in impaired development of mammary gland architecture and in reduced expansion of the mammary epithelium under the influence of female hormones during pregnancy. We are continuing to explore the role of impaired mammary stem cell function in breast cancer development.

Telomerase modulates Wnt signalling by association with target gene chromatin.
Index Medicus: Nature
Authors: Park JI, Venteicher AS, et al., and Artandi SE
Yr: 2009 Vol: 240 Nbr: Abs: Pg:66-72