Category Archives: Transhuman News

A leading gene candidate that has been the target of breast cancer drug development may not be as promising as initially thought, according to research published in open access journal Genome Medicine.

Mutation in the gene PIK3CA is the second most prevalent gene mutation in breast cancer and is found in 20% of all breast cancers. This has led people to think these changes may be driving breast cancer. Yet these mutations are also known to be present in neoplastic lesions -pre-cancerous growths many of which are thought to be benign, that have not invaded the surrounding tissue.

Researchers from Stanford University wanted to better understand these neoplastic growths and how they related to the carcinoma. They sequenced the genes from tissue taken from the breasts of six women who had undergone a mastectomy, leading to a total of 66 samples, which included 18 carcinomas and 34 neoplastic lesions.

A specific mutation in the PIK3CA gene occurs in the same patient multiple times. This was found to be the case for four out of the six women. In two out of these four cases, this mutation occurs in the neoplastic lesions, which are not considered tumors, but does not occur in the invasive carcinoma.

One of the lead researchers, Arend Sidow, said: "There are currently several drugs in development that target PIK3CA, attesting to the fact that many companies and clinicians believe PIK3CA to be a promising target. Our finding that PIK3CA may recur multiple times at various stages of tumor or neoplastic development suggests that it is more of a moving target than one would like."

The researchers constructed phylogenetic trees to track the mutations back to their original cell to determine how the lesions were related to each other. From this, the researchers discovered that in each of the four PIK3CA-positive patients the mutation arose independently multiple times. This is something that has never been seen before. Following the PIK3CA mutation through these phylogenetic trees, and its lack of presence in the final carcinoma in two cases, would suggest that it is not driving the cancer, and instead suggests that it is a driver of benign proliferation.

This new information will have implications for the development of future drugs that target PIK3CA. Future studies should attempt to replicate this one with more patients and attempt to show whether PIK3CA mutations are ancestrally present in the tumor cells of positive patients, in which case it may be good target, or whether it is present in only a subset of tumor cells, in which case it is not a good target.

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We may be looking at wrong mutation for breast cancer treatment

Study advances understanding of neurological circuits that might be targeted to treat anorexia nervosa

Building on their discovery of a gene linked to eating disorders in humans, a team of researchers at the University of Iowa has now shown that loss of the gene in mice leads to several behavioral abnormalities that resemble behaviors seen in people with anorexia nervosa.

The team, led by Michael Lutter, MD, PhD, assistant professor of psychiatry in the UI Carver College of Medicine, found that mice that lack the estrogen-related receptor alpha (ESRRA) gene are less motivated to seek out high-fat food when they are hungry and have abnormal social interactions. The effect was stronger in female mice, which also showed increased obsessive-compulsive-like behaviors.

The study also shows that ESRRA levels are controlled by energy status in the mice. Restricting calorie intake to 60 percent of normal over several days significantly increased levels of ESRRA in the brains of normal mice.

"Decreased calorie intake usually motivates animals, including humans, to seek out high-calorie food. These findings suggest that loss of ESRRA activity may disrupt that response," Lutter says.

Anorexia nervosa and bulimia nervosa are common and severe mental illnesses. Lutter notes that although 50 to 70 percent of the risk of getting an eating disorder is inherited, identifying the genes that mediate this risk has proven difficult.

ESRRA is a transcription factor - a gene that turns on other genes. Lutter and his colleagues previously found that a mutation that reduces ESRRA activity is associated with an increased risk for eating disorders in human patients. Although ESRRA is expressed in many brain regions that are disrupted in anorexia, almost nothing was known about its function in the brain. In the new study, published online April 9 in the journal Cell Reports, Lutter's team manipulated ESRRA in mice to investigate the gene's role in behavior.

"This work identifies estrogen-related receptor alpha as one of the genes that is likely to contribute to the risk of getting anorexia nervosa or bulimia nervosa," Lutter says. "Clearly social factors, particularly the western ideal of thinness, contribute the remaining 'non-genetic' risk, and the increasing rate of eating disorders over the past several decades is likely due to social factors, not genetics," he adds.

Through a series of experiments with genetically engineered mice, Lutter and his team showed that mice without the ESRRA gene have behavioral abnormalities related to eating and social behavior. In particular, mice without ESRRA show reduced effort to work for high-fat food when they are hungry. The mice also exhibited impaired social interaction and female mice without the gene show increased compulsive grooming, which may mimic obsessive-compulsive-type behavior in humans.

In order to refine their understanding of the effects of ESRRA in the brain, the researchers selectively removed the gene from particular brain regions that have been associated with eating disorders. They found that removing the gene from the orbitofrontal cortex was associated with increased obsessive-compulsive-type behaviors in female mice, while loss of ESRRA from the prefrontal cortex produced mice that were less willing to work to get high-fat food when they were hungry.

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Gene loss creates eating disorder-related behaviors in mice