Monthly Archives: April 2015

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

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

Using induced pluripotent stem cells (iPSCs), a team led by Mount Sinai researchers has gained new insight into genetic changes that may turn a well known anti-cancer signaling gene into a driver of risk for bone cancers, where the survival rate has not improved in 40 years despite treatment advances.

The study results, published today in the journal Cell, revolve around iPSCs, which since their 2006 discovery have enabled researchers to coax mature (fully differentiated) bodily cells (e.g. skin cells) to become like embryonic stem cells. Such cells are pluripotent, able to become many cell types as they multiply and differentiate to form tissues. The iPSCs can then be converted again as needed into differentiated cells such as heart muscle, nerve cells, bone, etc.

While some seek to use iPSCs as replacements for cells compromised by disease, the new Mount Sinai study sought to determine if they could serve as an accurate model of genetic disease "in a dish." In this context, the dish stands for a self-renewing, unlimited supply of iPSCs or a cell line - which enables in-depth study of disease versions driven by each person's genetic differences. When matched with patient records, iPSCs and iPSC-derived target cells may be able to predict a patient's prognosis and whether or not a given drug will be effective for him or her.

In the current study, skin cells from patient with and without disease were turned into patient-specific iPSC lines, and then differentiated into bone-making cells where both rare and common bone cancers start. This new bone cancer model does a better job than previously used mouse or cellular models of "recapitulating" the features of bone cancer cells driven by key genetic changes.

"Our study is among the first to use induced pluripotent stem cells as the foundation of a model for cancer," said lead author Dung-Fang Lee, PhD, a postdoctoral fellow in the Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai. "This model, when combined with a rare genetic disease, revealed for the first time how a protein known to prevent tumor growth in most cases, p53, may instead drive bone cancer when genetic changes cause too much of it to be made in the wrong place."

Rare Disease Sheds Light on Common Disease

The Mount Sinai disease model research is based on the fact that human genes, the DNA chains that encode instructions for building the body's structures and signals, randomly change all the time. As part of evolution, some code changes, or mutations, make no difference, some confer advantages, and others cause disease. Beyond inherited mutations that contribute to cancer risk, the wrong mix of random, accumulated DNA changes in bodily (somatic) cells as we age also contributes to cancer risk.

The current study focused on the genetic pathways that cause a rare genetic disease called Li-Fraumeni Syndrome or LFS, which comes with high risk for many cancers in affected families. A common LFS cancer type is osteosarcoma (bone cancer), with many diagnosed before the age of 30. Beyond LFS, osteosarcoma is the most common type of bone cancer in all children, and after leukemia, the second leading cause of cancer death for them.

Importantly, about 70 percent of LFS families have a mutation in their version of the gene TP53, which is the blueprint for protein p53, well known by the nickname "the tumor suppressor." Common forms of osteosarcoma, driven by somatic versus inherited mutations, have also been closely linked by past studies to p53 when mutations interfere with its function.

Rare genetic diseases like LFS are good study models because they tend to proceed from a change in a single gene, as opposed to many, overlapping changes seen in more related common diseases, in this case more common, non-inherited bone cancers. The LFS-iPSC based modeling highlights the contribution of p53 alone to osteosarcoma.

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Stem cell disease model clarifies bone cancer trigger