Understanding Telomere Dynamics in the Breast

Institution: Stanford University
Investigator(s): Steven Artandi, M.D., Ph.D. -
Award Cycle: 2002 (Cycle VIII) Grant #: 8PB-0155 Award: $681,564
Award Type: Request for Applications
Research Priorities
Biology of the Breast Cell>Biology of the Normal Breast: the starting point



Initial Award Abstract (2002)
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.


Final Report (2006)
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 expressed 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 proliferate. 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 involves 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 breast cancer.

During the final year of this proposal, we made important progress on the aims of this three year proposal. Aim one is to understand how telomere shortening in a model system alters the normal breast. To study this process in mice, we have successfully created new genetically engineered mice that lack TERT, the protein component of telomerase. We have shown that these mice lack telomerase and that their telomeres shorten with aging, as do human telomeres. We hypothesize that telomere dysfunction the telomere breakdown that occurs with aging will impair mammary tissue function. We have now shown that telomere dysfunction dramatically impairs the function of mammary stem cells. The mammary gland is maintained by stem cells that can give rise to all mammary epithelial types. We anticipate that in cells that retain p53, telomere shortening will lead to very high rates of cell suicide, or programmed cell death. In cells that have lost p53, we hypothesize that early breast cancers will begin to form. I believe that this study may be a good model system for understanding how DCIS forms in women. In Aim 2, we have constructed a genetically engineered system to allow us to reactivate telomerase and model how telomerase reactivation seen in 90-100% of human DCIS and human breast cancers allows cancers to mature. We have shown that using a special virus, we can indeed reactivate telomerase in normal breast cells. We are currently preparing a manuscript for publications detailing how telomere shortening with advancing age impairs the function of mammary stem cells and we are continuing to study how this process leads to DCIS and invasive breast cancer.

Over the past three years we have gained critical new insights into how telomeres alter mammary stem cells with advancing age. These results have important implications for understanding how early cancers form and how early cancers develop into potentially life threatening tumors that spread throughout the body. These insights are necessary to devise novel means of interfering with this process of breast cancer development and bringing new therapies to the clinic.


Symposium Abstract (2005)
Introduction: In spite of the exciting progress made in the last few years in our understanding of breast cancer the molecular events underlying breast carcinoma remain incomplete and has complicated the efforts to develop rational therapies for treating breast cancer. The vast majority of human breast cancers are characterized by the presence of unstable chromosomes. One of the ways chromosomes break down is when the sequences they have at their ends called telomeres become very short. Telomeres are made by a special enzyme called telomerase. Most human cells do not express telomerase and our telomeres shorten as we age and limit the ability of our cells to proliferate. Cancer cells however learn to reactivate telomerase and this allows them to proliferate indefinitely. Mouse models of human diseases such as breast cancer have enormous potential in contributing to our understanding of the genetic and molecular basis behind the diseases and will help us in developing novel strategies for clinical treatment. We have built a novel mouse model that will accurately represent the chromosomal instability that occurs in human breast cancer.

Experimental procedures: We have used genetic engineering technology to create a mouse in which a simple genetic trick keeps the telomerase enzyme turned off and allows telomere shortening resembling the event that accompanies aging and chromosomal break down in all humans. We will study breast cancer formation in these mice. We will use new technologies to study the molecular changes in these tumors and use this information to understand human breast cancer.

Results: We have performed a thorough characterization of the novel mouse we generated. We show that when the telomerase enzyme is turned off, the mice have short telomeres, which impairs stem cell function in several tissues including mammary gland. We are currently studying the effects of telomere dysfunction on cancer formation.

Potential outcomes: We hope that the findings from this study will enable us to better understand the events that drive breast cancer formation, especially the earliest steps in breast cancer formation, and aid in developing better preventive and therapeutic strategies.