June 1, 2009 -- Researchers at the University of Michigan have identified a gene that may be involved in as many as one in five breast cancers. And the gene could be blocked by a common blood pressure drug.
The gene, AGTR1, caused normal breast cells to act like highly invasive cancer cells, both in the laboratory and in mice. When the mice were then treated with an FDA-approved blood pressure drug, losartan, tumors that overexpressed AGTR1 shrunk by 30% within eight weeks.
The Hunt for Breast Cancer Genes
The researchers identified AGTR1 by using gene expression profiling data to compare thousands of genes that might be linked to breast cancer. AGTR1 was overexpressed (or overly productive of its gene product) in 10% to 20% of all breast cancers -- second only to HER2, which is found in 25% to 30% of all breast cancers and responds well to the drug Herceptin.
“HER2 ... makes breast cells cancer-like. That’s very similar to what we found with AGTR1,” says Daniel Rhodes, PhD, a research investigator in the Michigan Center for Translational Pathology and the lead author of the study, which appears in the June 1 edition of Proceedings of the National Academy of Sciences. Rhodes is also the founder and CEO of a cancer genomics company, Compendia Biosciences.
Breast cancer researchers have been looking for other targets similar to HER2 in order to develop more targeted treatments for women whose breast cancers are not HER2-positive and therefore do not respond to Herecptin.
Blood Pressure Drugs for Breast Cancer
Because AGTR1 is involved in the constriction of blood vessels, its activity is blocked by a class of drugs called angiotensin receptor blockers, which include losartan, the drug tested in this study. “This is particularly exciting, because losartan is such a safe and widely prescribed therapy,” Rhodes says. “This makes it much easier to do a clinical trial.”
If losartan really does block the cancer-promoting activity of AGTR1, why hasn’t anyone identified a lower rate of breast cancer among women taking the drug for high blood pressure?
“One would expect epidemiologic studies to show a reduction in BC [breast cancer] risk in people taking this drug,” says Clifford Hudis, MD, chief of the breast cancer medicine service at Memorial Sloan-Kettering Cancer Center in New York. “I don’t remember ever seeing hypertension and treatment for hypertension as indicators of lower breast cancer risk. We have lots of patients who get treated for breast cancer and take anti-hypertensives, so you would expect to see that pop out as an indicator of good outcomes.”
But not all high blood pressure drugs specifically block the AGTR1 receptor. “We think that true blockers to the AGTR1 protein would have the strongest effect, and these drugs, like losartan, are generally used as second-line therapies for hypertension,” Rhodes tells WebMD. "If only a few women in 100 are being treated with angiotensin receptor blockers, and only 10% to 20% of all breast cancers are AGTR1-positive, you’d need thousands of patients to see an effect.”
Developing a Test for AGTR1-Positive Tumors
But if there were a study in which losartan were given only to women with breast cancers linked to overexpression of AGTR1, it would be much easier to detect an effect. Before such a trial can be set up, however, scientists must first develop a way to easily detect AGTR1 overexpression.
Once that test is available -- something that should take only a few months, says Rhodes -- a clinical trial should be easier than usual to set up because of the availability of an existing, approved therapy whose side effects are known. “No trial is specifically planned yet, but we are talking with our clinical colleagues about it and there is a great deal of interest,” he says.
“If the data can be confirmed, it’s not a big stretch to imagine setting up a randomized study relatively easily,” Hudis says. “I definitely think this should be investigated further, although as always when we don’t yet have data in humans, you have to be careful and not jump to conclusions.”
The University of Michigan has filed a patent on AGTR1 and is seeking commercial partners.