Breast cancer is the most common cancer in women and is responsible for over 400,000 deaths annually in women throughout the world. Most of these deaths are the result of aggressive breast tumors that often fail to respond to current treatments.
The researchers found that women whose breast tumors express the alphaB-crystallin protein have a shorter survival, suggesting that alphaB-crystallin may be a useful molecular marker to identify women with aggressive breast cancer and to develop new targeted cancer therapies.
The study, which was published in the January issue of the Journal of Clinical Investigation, was led by Vincent L. Cryns, M.D., associate professor of medicine and director of the Cell Death Regulation Laboratory at Northwestern University Feinberg School of Medicine, and a researcher at The Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
Cryns and colleagues found that introducing the alphaB-crystallin gene into non-cancerous breast cells transformed them into breast cancer cells. These experiments took advantage of a powerful technique to grow breast cells as three-dimensional (3D) gland-like structures that are similar to those present in the normal breast. However, when the researchers introduced alphaB-crystallin into non-cancerous breast cells, the cells started growing uncontrollably and formed enlarged 3D masses that resemble breast tumors.
The experiments were conducted by Jose V. Moyano, a post-doctoral fellow in the Cryns lab, who was lead author on the study.
"Basically, breast cancer cells have hijacked alphaB-crystallin, a protein that normally protects cells against stress injury and death, and used it to promote their uncontrolled growth," Cryns reflected.
The investigators also showed that alphaB-crystallin activates a key molecular pathway, the MEK-ERK pathway, that leads to unrestrained cell growth in cancer, and that drug inhibitors of this pathway block the cancerous effects of alphaB-crystallin.
"Currently, we don't have any targeted treatments like tamoxifen or Herceptin for the aggressive type of breast tumors that express alphaB-crystallin. Our results suggest that these tumors may respond to drugs that block this important pathway activated by alphaB-crystallin," Cryns said.
Cryns' laboratory group also observed that non-cancerous breast cells genetically manipulated to express alphaB-crystallin form aggressive breast tumors when injected into mice, confirming their malignant nature.
What's more, the team found that these mouse tumors were similar in many respects to human breast tumors which express alphaB-crystallin, suggesting that this mouse model may be useful for testing new treatments for these poor-prognosis tumors. Indeed, the researchers are currently exploring whether drug inhibitors of the MEK-ERK pathway block breast tumor growth in mice.
Collaborating with Cryns and Moyano were Torsten O. Nielson and Dmitry Turbin, University of British Columbia, Vancouver; and Charles M. Perou and Gamze Karaca, University of North Carolina at Chapel Hill. Other members of the research team at Northwestern University were Fruma Yehiely, Joseph R. Evans, Feng Chen, Meiling Lu, Michael E. Werner, Leslie Diaz and Elizabeth Wiley.
This research was supported by grants from the National Institutes of Health, including Specialized Programs of Research Excellence in Breast Cancer at Northwestern University and the University of North Carolina at Chapel Hill; the Department of Defense Breast Cancer Research Program; the Avon Foundation Breast Cancer Research and Care Program; and the Michael Smith Foundation for Health Research.