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Scientists identify two key genes linked to aggressive breast cancers

September 15, 2005

Drugs already in development to target the genetic pathway

(Toronto) - In a new study, scientists at The Hospital for Sick Children and Princess Margaret Hospital have shown that two genes called Notch1 and Jagged1 are linked to more aggressive breast cancers and that patients are less likely to survive the disease when these two genes are highly expressed.

The study is published in the September 15th issue of the journal Cancer Research, a publication of the American Association for Cancer Research.

"These two genes are likely markers indicating a patient's probable prognosis," says the study's principal investigator Dr. Sean Egan, senior scientist at The Hospital for Sick Children and associate professor of molecular and medical genetics at the University of Toronto. "Now we can develop a way of screening for these markers, which may help physicians determine how best to treat patients."

Notch1 and Jagged1 are players in the Notch signalling pathway, which is normally involved in cell communication, division, differentiation, survival, and self-renewal. The scientists' work suggests that the Notch pathway may be overactive in some aggressive breast cancers.

"We're excited by this discovery because there are drugs already in development that interfere with the Notch pathway," says the study's lead author Dr. Michael Reedijk, surgical oncologist in the breast cancer program at Princess Margaret Hospital and assistant professor of surgery at the University of Toronto. "We're benefiting from 10 years of research that's been done on generating drugs to treat Alzheimer's disease. These drugs inhibit an enzyme called gamma secretase, which is likely responsible for the build up of amyloid plaques in the brains of patients with Alzheimer's disease. As Notch signalling also depends on gamma secretase, these drugs may be useful in treating Notch-dependant cancers."

The scientists examined tumour samples from 184 breast cancer patients with different prognoses and compared the gene expressions with each patient's outcome. Patients with high levels of Jagged1 had a five-year survival rate of 42% and an average survival of 50 months, compared to patients with low levels of Jagged1 who had a five-year survival rate of 65% and an average survival of 83 months.

Patients with high levels of Notch1 had a five-year survival rate of 49% and an average survival of 53 months, whereas patients with low levels of Notch1 had a five-year survival rate of 64% and an average survival of 91 months.

Patients with combined high levels of Jagged1 and Notch1 had a significantly reduced five-year survival rate of 34% and an average survival of 43 months.

Breast cancer is the most commonly diagnosed cancer and a leading cause of cancer death. The Canadian Cancer Society estimates that 21,600 women will be diagnosed with breast cancer and 5,300 will die of the disease in 2005. One in nine women will develop breast cancer during her lifetime, and one in 27 women will die from breast cancer.

University of Toronto