Origins of Deadliest Breast Cancer Identified at Duke
DURHAM, N.C. -- Scientists have discovered that loss of a critical protein in breast cells can initiate a particularly aggressive and often fatal form of cancer called "basal type" breast cancer.
They said their discovery is important for identifying women at increased risk for basal-type breast cancer and for developing new drugs that more effectively target this treatment-resistant cancer. Early detection is particularly important because the disease strikes young women of child-bearing age and typically resists chemotherapy and other front-line drugs, said the researchers from the Duke Comprehensive Cancer Center.
The Duke scientists found that basal-type breast cells which lose expression of the CREB-binding protein (CBP) are unable to engage in programmed cell death or "apoptosis," so the cells over-proliferate. Apoptosis is a critical defense mechanism that cells use to commit suicide when they become irreparably damaged or are no longer needed by the body.
Results of the study are published in the Nov. 1, 2005, issue of the Journal of Cell Science. The research was sponsored by the National Cancer Institute, the V-Foundation, the Avon Foundation, the Susan G. Komen Breast Cancer Foundation and the Charlotte Geyer Foundation.
"There hasn't been a good model of basal-type breast cancer, so we haven't understood how this type of cancer starts and thus how to prevent or eradicate it," said Victoria Seewaldt, M.D., director of the Breast Health Clinic at Duke and senior author of the study. "Our discovery provides a critical clue as to how basal-type breast cancer might start, and this knowledge gives us the power to detect early changes that lead to this type of breast cancer."
Seewalt's study is an integral part of her teams' effort to develop better ways to detect early changes in the breast that give rise to cancer. It is critical to determine which of the many changes in breast cells – alone or in combination – will progress to become invasive breast cancer and which changes are benign. She said the current study identifies a group of deleterious changes, including CBP loss, which put women at the highest risk of developing this aggressive form of breast cancer.
Researchers at University of North Carolina at Chapel Hill first identified basal-type breast cancer in 2003 based on its unique pattern of gene expression. Its signature traits include the expression of a protein called cytokeratin 5/6, the loss or mutation of the p53 gene, and the frequent absence of estrogen or progesterone receptors and the Her2/neu protein. Treatments aimed at suppressing these elements are ineffective against most basal type cancer cells because they generally don't produce those elements, said Seewaldt.
In fact, basal-type carcinoma defies all the usual principles of breast cancer onset, said Seewalt. It often strikes young women in their 30s, and women who have given birth before the age of 30. Typically, childbirth before the age of 35 is protective against breast cancer, but this protective effect does not seem to apply to basal-type cancers. The disease strikes young African-American women disproportionately, said Seewaldt, making a diagnosis of breast cancer especially concerning for this population.
To characterize the disease, Seewaldt's team analyzed basal-type breast cells from both young African-American and Caucasian women. They studied specific signaling pathways the body uses to eliminate cells that develop a mutation or loss of P53, a tumor suppressor gene. Cells that lack a functioning P53 gene, then subsequently lose CBP or its downstream target — the laminin 5 protein -- can no longer undergo apoptosis, said Seewaldt.
Although losing CBP does not guarantee cancer, cells that have also lost CBP protein appear to have lost their ability to eliminate themselves once they become damaged, said Seewaldt. Moreover, CBP is thought to be important for allowing another breast cancer gene, BRCA1, to repair DNA. Thus, loss of CBP in a woman who has a mutation in the BRCA1 gene may put her at extremely high risk for developing breast cancer, said Seewaldt.
"If we find atypical breast cells in a woman, meaning they are abnormal but not cancerous, and then we find loss of CBP, we would hypothesize that this woman is at very high risk for developing breast cancer in the future," said Seewaldt. "We think that loss of CBP in women who carry the BRCA-1 mutation may be especially important for helping us predict future risk."
Seewaldt's team has been instrumental in coupling a new research test, Random Periareolar Fine Needle Aspiration – dubbed the "breast pap smear" – with sensitive new molecular tests. Together, these methods can detect early changes in breast tissue and determine which early changes may lead to breast cancer. Random Periareolar Fine Needle Aspiration was first developed by Carol Fabian, M.D., at University of Kansas. The new test enable researchers to test breast cell for specific molecular changes that may precede breast cancers and help women track whether they are responding to preventive agents.
Seewaldt's goal is to ultimately identify early breast cancers by their molecular signatures, then prescribe targeted prevention agents aimed at each specific breast cancer type. Basal-type carcinoma is her most formidable opponent.
"I remember my patients with basal-type breast cancer as the mothers whose children I write letters to, explaining that, despite our best efforts, we couldn't save their mommies," said Seewaldt. "In my lifetime, and hopefully in the near future, I want to change that outcome."