Scientists Identify Two Key Genes Linked To Aggressive Breast Cancers

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

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

Notch1 and Jagged1 are players in the Notch signalling pathway, which is normally involved incell communication, division, differentiation, survival, and self-renewal. The scientists' worksuggests 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 interferewith the Notch pathway," says the study's lead author Dr. Michael Reedijk, surgical oncologistin the breast cancer program at Princess Margaret Hospital and assistant professor of surgery atthe University of Toronto. "We're benefiting from 10 years of research that's been done ongenerating drugs to treat Alzheimer's disease. These drugs inhibit an enzyme called gammasecretase, which is likely responsible for the build up of amyloid plaques in the brains of patientswith Alzheimer's disease. As Notch signalling also depends on gamma secretase, these drugsmay be useful in treating Notch-dependant cancers."

The scientists examined tumour samples from 184 breast cancer patients with differentprognoses 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 survivalof 50 months, compared to patients with low levels of Jagged1 who had a five-year survival rateof 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 survivalof 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-yearsurvival 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. TheCanadian Cancer Society estimates that 21,600 women will be diagnosed with breast cancer and5,300 will die of the disease in 2005. One in nine women will develop breast cancer during herlifetime, and one in 27 women will die from breast cancer.

This research is supported by funds from The Terry Fox Foundation and SickKids Foundation.Dr. Reedijk holds the James Ewing Oncology Fellowship for Basic Research from the Society ofSurgical Oncology. He is supported by the Departments of General Surgery at University HealthNetwork and Mount Sinai Hospital and by the Department of Surgery at the University ofToronto. SickKids Foundation provided salary and infrastructure support to Dr. Egan.

The Hospital for Sick Children, affiliated with the University of Toronto, is Canada's mostresearch-intensive hospital and the largest centre dedicated to improving children's health in thecountry. Its mission is to provide the best in family-centred, compassionate care, to lead inscientific and clinical advancement, and to prepare the next generation of leaders in child health.

Princess Margaret Hospital and its research arm, Ontario Cancer Institute, have achieved aninternational reputation as global leaders in the fight against cancer. The Campbell FamilyInstitute for Breast Cancer Research is the newest component of the Ontario Cancer Institute. Itaims to become a world-leading program in breast cancer research by leveraging basic,translational, and clinical research into dramatic breast cancer breakthroughs. Princess MargaretHospital is a member of the University Health Network, which also includes Toronto GeneralHospital and Toronto Western Hospital. All three are teaching hospitals affiliated with theUniversity of Toronto.