U.S. researchers have discovered a mechanism that may lead to ways to predict and perhaps interfere with the formation and development of cancer.
Researchers at the University of California, San Diego School of Medicine have pinpointed a mechanism that may help explain how chromosomal
translocations -- the supposedly random shuffling of large chunks of DNA that frequently lead to cancer -- are not so random after all.
They have developed a model of such chromosomal mix-ups in prostate cancer that indicates that the male sex hormone (androgen) receptor unexpectedly plays a key role in driving specific translocations in the development of cancer.
Researchers found that under certain conditions involving some sort of genetic "stress" -- such as cigarette smoke, a toxic chemical exposure or radiation, the androgen receptor can act in concert with several key enzymes and pathways induced by genotoxic stress to unexpectedly direct specific translocations leading to cancer.
Dr. Michael G. Rosenfeld, lead author of the study and professor of medicine at the UC San Diego School of Medicine, said that in the future, one goal would be to find tumor-causing translocations in breast and other cancers and develop a chemical library screen to find compounds that might inhibit these events.
He explained that chromosome mix-ups are a hallmark of leukemias and lymphomas and, increasingly, other cancers such as more aggressive forms of prostate cancer.
It has been known to scientists that various types of genetic stress can lead to random breaks in DNA and rearrangements in chromosomes,
resulting in excessive cell growth and cancer, but the exact mechanisms have been poorly understood.
The UC San Diego research team created a tumor translocation model in prostate cancer and found that instead of random DNA breaks, the breaks were in specific chromosomal areas bound by the androgen receptor that directed the pattern of cancer-causing translocations.
Researchers from Rosenfeld's group identified several mechanisms, some involving specific enzymatic pathways that worked together with the androgen receptor to form specific translocations.
"Our findings suggest that sex steroid receptors -- androgen and estrogen receptors -- can cause mutations when in the presence of genotoxic stress, and form site-specific chromosomal translocations, " Rosenfeld said.
He said understanding the molecular mechanisms that underlie tumor translocations and the specific strategies used by normal cells to protect against such rearrangements could provide insights into cancer development and eventually help in the development of new therapeutic approaches.
The study was published on line Dec. 3 in advance of publication in the journal Cell.