Advances in Breast Cancer Research

Fall 2005

This year, more than 40,000 women in the U.S. will die from breast cancer. That's nearly 15 times the number of people killed as a result of the 9/11 terrorist attacks.

If you could identify in advance those at high risk to develop breast cancer, perhaps fewer woman would die from this disease. SAIC-Frederick's Stephen Lockett (and colleagues) are working toward this goal. In their SAIC's Executive Science & Technology Council (ESTC) Award-winning paper, they report on a dramatic increase in the level of "genomic instability" (genetic diversity and instability from cell to cell) in later stages of the disease.

Telomere crisis

The researchers hypothesize that genomic instability might be associated with a "telomere crisis," which is thought to be a crucial event in the development of most breast carcinomas.

Located at the end of a chromosome, "telomeres" serve to assure that a chromosome replicates properly each time a cell divides. But excessive cell division causes telomeres to shorten (and chromosomes to stick together), which can lead to cell death. This process ― the telomere crisis ― normally protects against inappropriate long-term cell growths such as cancer. However, some cells can survive and an enzyme ― telomerase ― may be turned on in these cells, restoring telomeres for the now aberrant chromosome.

In fact, the researchers speculate that cells in which telomerase is activated can proliferate indefinitely to form the next stage of cancer, known as ductal carcinoma in situ (localized and confined to one area). Should the cancer progress further, it will invade other parts of the breast and may escape to various organs, a process known as metastases.

Assessments and findings

By using 3-D confocal microscopy and working first with breast cancer tissue samples, the researchers assessed, at each histological stage, genomic instability and correlated features such as the amount of DNA content, signs of rearranged chromosomes, and the number of copies of genes known to play a role in cancer. These measures increased, on average, from the hyperplasia stage to the invasive cancer stage.

The researchers also found that telomere length decreased from normal tissue to carcinoma in situ, and decreased even more in invasive cancers. When they looked at cultured human mammary cells, the researchers found a remarkably similar series. The mammary cell culture studies also confirmed that it's tough for damaged cells to successfully pass through the telomere crisis ― most cells that have been damaged from shortened telomeres can't evade cell death. In fact, women with usual ductal hyperplasia are only slightly more at risk of developing invasive cancer. When carcinoma in situ does form, it is probably from a small minority of cells that have managed to reactivate telomerase.

Identifying risk

In conclusion, the researchers established that the telomere crisis appears to play an important role in the development of most breast cancers and also established where the telomere crisis occurs ― at the transition from the hyperplasia stage to carcinoma in situ.

These findings suggest that people at higher risk of developing cancer can be identified in the clinic, in advance, by measuring telomerase activity, genome instability, and other signals. The findings also point to possible ways of stopping cancer ― by derailing transition through the telomere crisis using drugs that maintain the cell's damage-control mechanisms, prevent telomerase reactivation, or drugs that poison cells where telomerase is already active.

Lockett's paper, "In situ analyses of genome instability of breast cancer," appeared in Nature Genetics.

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