Although preliminary, a recent experimental study published online in the journal Genetics (Wallace MD, et al. Genetics. 2012;192:
385-396) found that lack of the neurofibromin 1 (NF1) gene was observed in more than 1 of every 4 experimentally induced breast cancers. The study findings also suggest that tamoxifen will not be effective in cancers that lack the NF1 gene.
This research—if borne out in humans—will have huge implications for the estimated 60,000 new cases of breast cancer that will be diagnosed in the United States and the 383,000 cases that will be diagnosed worldwide in 2012.
In the study, the NF1 gene was missing in about 28% of breast cancers. Previous studies have shown that NF1 depletion causes tamoxifen resistance, and patients with tumors that have low NF1 levels had worse outcomes on tamoxifen.
The NF1 gene has negative effects on the RAS oncogene, which is involved in intracellular signaling that controls cell growth. When NF1 is lacking, RAS becomes hyperactivated and can lead to tumor proliferation.
The study employed a mouse model with elevated mutation rates that led to breast cancers in 80% of the animals. When the researchers looked at the genomes of mice that developed mammary tumors, nearly all were missing the NF1 gene, explained senior author of the paper, John Schimenti, PhD, professor of genetics at the College of Veterinary Medicine, Cornell University, Ithaca, New York.
Human breast cancers have many causes, and each patient’s tumor has a unique set of gene variants as well as new mutations, making it extremely difficult to identify individual genes that drive the cancer, explained Schimenti in a press release from Cornell. The mouse model used in the study is inbred, and the mice get exactly the same type of tumor every time, eliminating “noise” and allowing the researchers to identify NF1 as a driver of these mutations, according to the press release.
RAS is hyperactivated in the mouse model for breast cancer. Chemotherapy agents that interrupt the RAS pathway are available for the treatment of breast cancer, and it is possible that these drugs will be effective in breast cancers that have low levels of NF1 or cancers with a missing NF1 gene.
The Cornell researchers plan to study whether insertion of a replacement NF1 gene can reverse tumor growth in mice lacking the gene. They are also studying whether RAS inhibitors can slow the growth of breast cancer in the mouse model. In the paper, the researchers stated that RAS inhibitors could slow tumor cell growth in vitro.
Marsha Wallace, a graduate student at Cornell, was lead author of the paper. The authors note that the loss of NF1 may trigger activation of other pathways in addition to RAS, and it will be important to understand these effects as well.