Biology of Telomere Length Conservation in Breast Cancer

Institution: University of Southern California
Investigator(s): Darryl Shibata, M.D. -
Award Cycle: 1995 (Cycle I) Grant #: 1IB-0121 Award: $78,798
Award Type: IDEA
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease

Initial Award Abstract (1995)
Breast cancer is likely a heterogeneous disease which occurs after the accumulation of many different genetic alterations. This heterogeneity complicates diagnostic and prevention advances since multiple approaches are necessary. However, all dividing cells suffer from the shortening of their chromosomes since normal cells cannot copy chromosomal ends (telomeres). The progressive loss of telomeres prevents normal cells from dividing forever. In contrast, breast cancer cells can divide forever and kill because they abnormally express an enzyme (telomerase) which repairs telomeres. The transition between telomerase-negative and telomerase-positive breast cells marks a critical conversion between cells which cannot divide forever and cells which are immortal. Therefore, a single telomerase assay can potentially identify all "immortal" or tumor breast cells from any patient. Combined with the high specificity of telomerase activity for cancer, this highly sensitive assay may facilitate the molecular detection of breast cancer.

It is unknown when telomerase activity is expressed in breast cancer. Since many breast cancers contain both early and late tumor regions, micro-dissection of these regions followed by telomerase detection may identify whether it is produced very early or late in breast cancer development. A newly developed assay based on the polymerase chain reaction allows the sensitive detection of telomerase activity from as few as one cancer cell. Characterization of when telomerase is expressed during breast cancer progression should help identify tumorigenic factors which induce its abnormal production, and further identify the assay's potential to detect very early breast cancers.

Final Report (1997)
Breast cancers grow until they kilI. One barrier to unlimited cellular growth is the inability of all cells to completely copy the ends of their chromosomes during normal DNA replication prior to cell division. Thus, with repeated cell division the ends of the chromosomes (telomeres) become progressively shorter until the chromosome and gene function become defective. Normally, this chromosomal shortening caps the potential number of cell divisions to about 100. However, cancer cells can overcome this limitation by expressing an enzyme, called telomerase, which repairs the chromosome ends. The objectives of this project were to characterize telomerase expression in breast cancer. Similar to most other cancers, telomerase expression was found in the majority of breast cancers (76%) and expression was detected in most (75%) early disease (in situ) samples. However, telomerase expression was found to be heterogeneous within a tumor suggesting that not all cancer cells require simultaneous telomerase activity. These findings were published this year.

The characterization of telomerase activity in breast cancer has the potential to assist in its early detection and therapy. Since telomerase expression is present in the majority of early breast cancers, relatively simple and sensitive telomerase assays could be employed to detect very early disease, when it is more easily treated. Agents that inhibit telomerase activity would be expected to be effective against early or late disease. However, the heterogeneous expression of telomerase in cancers suggest that strategies relying only on inhibition of telomerase activity may not be completely effective.

Telomerase activity in normal and neoplastic breast
Periodical:Clinical Cancer Research
Index Medicus: Clin Cancer Res
Authors: Tsao J-L, Zhao Y, Lukas J, Yang X, Shah A, Press M, and Shibata D
Yr: 1997 Vol: 3 Nbr: Abs: Pg:627-631