Altered cyclin E protein leads to genetic instability in breast cancer

December 03, 2003

SAN ANTONIO -- Researchers at The University of Texas M. D. Anderson Cancer Center have found a protein linked to poor outcome in breast cancer is often associated with genetic instability and increased resistance to endocrine therapy.

The study, presented at the San Antonio Breast Cancer Symposium, provides a molecular model for the 25 percent of breast cancer patients who have high levels of "low molecular weight" cyclin E in their tumors.

"We want to come up with a better mode of therapy for patients with this form of cyclin E and this model system may provide a biological tool for drug targeting," says the study's lead researcher, Khandan Keyomarsi, Ph.D., associate professor in experimental radiation oncology.

Last year, Keyomarsi and her colleagues found in a study of about 400 patients that patients with high levels of low molecular weight cyclin E were significantly more likely to have an aggressive, invasive breast cancer. The protein, which is involved in regulation of a cell's living cycle, appears to be a much better predictor of patient outcome than any current predictive marker, says Keyomarsi, who reported the findings in the New England Journal of Medicine.

Currently, the prognosis for women diagnosed with breast cancer is determined by assessing whether tumor cells have spread to lymph nodes. But some women who have cancer cells in the lymph nodes never have a recurrence, while others whose cancer has not spread do have a recurrence. Yet many women undergo chemotherapy because of the uncertainty of their prognosis.

If an accurate predictive marker were available, many women could be spared chemotherapy, and those with the altered cyclin E protein may be offered more aggressive therapy from their initial diagnosis, Keyomarsi says.

Using the cell line model system in this study, led by Said Akli, Ph.D., an instructor in Keyomarsi's laboratory, the investigators found that low molecular weight cyclin E has the ability to make an otherwise estrogen-positive tumor unresponsive to anti-estrogen, endocrine therapy such as tamoxifen. "These tumors don't respond anymore to natural brakes in cell growth," she says. "They never get the brake signal to stop. More importantly, these altered forms have the ability to induce genetic instability, which is the hallmark of cancer," says Keyomarsi.

Keyomarsi then checked her findings in samples of tumors taken from patients, and found that patients who had not responded to either chemotherapy or endocrine therapy had the altered form of cyclin E. "Now that we understand what is happening on a molecular basis in these patients, we may be able to develop biological tools for drug targeting," she says.
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University of Texas M. D. Anderson Cancer Center

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