After mining the genetic records of thousands of breast cancer patients, researchers from the Johns Hopkins Kimmel Cancer Center have identified a gene whose presence may explain why some breast cancers are resistant to tamoxifen, a widely used hormone treatment generally used after surgery, radiation and other chemotherapy.

The gene, called MACROD2, might also be useful in screening for some aggressive forms of breast cancers, and, someday, offering a new target for therapy, says Ben Ho Park, M.D., Ph.D., an associate professor of oncology in the Kimmel Cancer Center’s Breast Cancer Program and a member of the research team.

The drug tamoxifen is used to treat oestrogen receptor-positive breast cancers. Cells in this type of breast cancer produce protein receptors in their nuclei which bind to and grow in response to the hormone oestrogen. Tamoxifen generally blocks the binding process of the oestrogen-receptor, but some oestrogen receptor-positive cancers are resistant or become resistant to tamoxifen therapy, finding ways to elude its effects. MACROD2 appears to code for a biological path to tamoxifen resistance by diverting the drug from its customary blocking process to a different way of latching onto breast cancer cell receptors, causing cancer cell growth rather than suppression, according to a report by Park and his colleagues.

Specifically, the team’s experiments found that when the gene is overexpressed in breast cancer cells–producing more of its protein product than normal–the cells become resistant to tamoxifen.

One piece of evidence for the gene’s impact was demonstrated when the Johns Hopkins scientists blocked MACROD2’s impact in breast cancer cell cultures by using an RNA molecule that binds to the gene to ‘silence,’ or turn off, the gene’s expression. But the technique only partially restored the cells’ sensitivity to tamoxifen.

To conduct the study, the scientists examined two well-known databases of breast cancer patients’ genetic information, The Cancer Genome Atlas and the Molecular Taxonomy of Breast Cancer International Consortium study. Patients who had MACROD2 overexpressed in primary breast cancers at the original breast cancer site had significantly worse survival rates than those who did not, according to an analysis of the patient databases.

With this in mind, the Johns Hopkins scientists suggest that clinicians may be able to look at MACROD2 activity to help them identify aggressive breast cancers at early stages of growth.

The team’s analysis also found that MACROD2 overexpression was present in the majority of metastases in patients with tamoxifen-resistant tumours and in tumour cells that had spread from their original site in the breast. The latter finding, says Park, suggests that tamoxifen resistance caused by the gene might be a process that develops over time as women take the drug.

Finding a small group of a patient’s cancer cells that overexpress MACROD2, he explained, means those cells are likely to be the ‘survivors’ of early treatment with tamoxifen that go on to multiply and cause metastatic tumours. ‘The resultant cells–or the vast majority of them–are now all overexpressing MACROD2, and are the cells that are aggressive and will cause trouble,’ he adds.

Park and his team cautioned that there may be other genetic factors that control tamoxifen resistance, and that nothing in their study should suggest that tamoxifen use should be avoided. EurekAlert

For some children with autism, the ‘Tooth Fairy’ lives in San Diego and wears a white coat. And the Tooth Fairy may offer an answer to what causes their autism, without painful blood draws or skin biopsies.

Alysson Muotri, associate professor of paediatrics and cellular molecular medicine at the University of California, San Diego, created this inventive project in 2012. He realized that rather than force children to undergo upsetting procedures, parents could simply mail one of their child’s baby teeth, which contain enough genetic information to eliminate the need for an in-person visit.

“We announced the project on social networks like Facebook,” Muorti says. “News spread fast.”

The project has roughly 3,500 registered families and 300 teeth so far, and researchers have found five autism candidate genes from the 20 or so cell lines they have sequenced. Several of those genes have never been implicated in autism before.

“We’re finding lots of new genes and sometimes we have no idea what they do, so the next step is to test whether or not those genes are important,” Muotri says. “This type of study may reveal novel pathways in autism and open up the possibility for personalized treatment.”

Autism’s cause is clear in a subset of cases, but the majority of cases are sporadic, meaning they arise from an unidentified combination of genetic and environmental factors.

“Every sporadic individual will likely carry several mutations that probably contribute to a certain extent to the disease, so it is really hard to model that complex phenotype,” Muotri says.

After receiving a tooth, the researchers extract cells from the dental pulp and sequence the whole genome to search for mutations associated with sporadic autism. They then use these dental cells to create induced pluripotent stem (iPS) cells, which can be coaxed into becoming neurons. Muotri says he and his colleagues are the first to use iPS-cell-derived human neurons to model sporadic autism. Simons Foundation Autism Research Institute

A new genetic finding from Duke Medicine suggests that some people who are prone to hostility, anxiety and depression might also be hard-wired to gain weight when exposed to chronic stress, leading to diabetes and heart disease.

An estimated 13 percent of people, all of whom are Caucasian, might carry the genetic susceptibility, and knowing this could help them reduce heart disease with simple interventions such as a healthy diet, exercise and stress management.

“Genetic susceptibility, psychosocial stress and metabolic factors act in combination to increase the risk of cardiovascular disease,” said Elizabeth Hauser, Ph.D. director of Computational Biology at the Duke Molecular Physiology Institute.

Hauser and colleagues analysed genome-wide association data from nearly 6,000 people enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA). The MESA study began in 2000 to better understand how heart disease starts, compiling the participants’ genetic makeup as well as physical traits such as hip circumference, body mass index, cholesterol readings, glucose levels, blood pressure and other measures.

In the Duke analysis, the researchers first pinpointed a strong correlation between participants who reported high levels of chronic life stress factors and increased central obesity, as measured by hip circumference.

They then tested genetic variations across the genome to see which ones, in combination with stress, seemed to have the biggest influence on hip circumference. It turns out that variations called single-nucleotide polymorphisms (SNPs) in the EBF1 gene showed a strong relationship with hip circumference, depending on levels of chronic psychosocial stress. What’s more, among those with this particular genotype, hips grew wider as stress levels increased.

“With further analysis, we found a significant pathway from high chronic life stress to wide hip circumference, to high blood glucose and diabetes, to increased cardiovascular disease, notably atherosclerosis,” said Abanish Singh, Ph.D., a researcher in computational biology at Duke and the study’s lead author. “But we found this only in people who were carriers of the EBF1 single-nucleotide polymorphism, and this was limited to participants who were white.”

The researchers reproduced their findings using data from another study, the Framingham Offspring Cohort.

“These findings suggest that a stress reduction intervention, along with diet and exercise, could reduce the risk of cardiovascular disease and may be most effective in individuals with this specific genotype,” said Redford Williams, M.D. one of the study’s senior authors and director of Duke’s Behavioral Medicine Research Center. Duke Medicine

New research by an international team including Keck Medicine of USC scientists is bringing the origins of ovarian cancer into sharper focus.

The study highlights the discovery of three genetic variants associated with mucinous ovarian carcinomas (MOCs), offering the first evidence of genetic susceptibility in this type of ovarian cancer. The research also suggests a link between common pathways of development between MOCs and colorectal cancer and for the first time identifies a gene called HOXD9, which turns genes on and off, and provides clues about the development of MOCs.

‘It remains a mystery where these cancers come from,’ said Simon Gayther, Ph.D., professor in preventive medicine, Keck School of Medicine of USC, corresponding author of the international genome-wide association study (GWAS). ‘By finding these genetic markers, we begin to understand more about the biology of the disease itself. This study tells us more about the biology of ovarian cancer from the early development stage than most research has.’

Ovarian cancer is the fourth leading cause of cancer in American women and seventh most common cancer in women throughout the world (World Health Organization). In 2015, more than 14,000 American women will die of ovarian cancer, according to the American Cancer Society.

Most ovarian cancers have low survival rates, typically because of the misunderstanding of symptoms and discovery of the cancer in later, less treatable stages. ‘Although MOCs are a less common type of ovarian cancer with generally good prognosis when diagnosed in early stages, they are twice as likely to be resistant to treatment at later stages,’ said Andrew Berchuck, M.D., director of gynecologic oncology at Duke University Cancer Institute, and senior author of the study. ‘Our results will contribute to the identification of women at greatest risk of developing the disease with the long-term goal of prevention.’

The association analysis was based on 1,644 women diagnosed with MOC and more than 21,000 women without ovarian cancer. The research was conducted as part of the Collaborative Oncological Gene-environment Study (COGS), launched in 2009 with the goal of determining risks of breast, ovarian and prostate cancer. EurekAlert

Practically everyone gets fatter as they get older, but some people can blame their genes for the extra padding. Researchers have shown that two different mutations in a gene called ankyrin-B cause cells to suck up glucose faster than normal, fattening them up and eventually triggering the type of diabetes linked to obesity.

The more severe of the two mutations, called R1788W, is carried by nearly one million Americans. The milder mutation, known as L1622I, is shared by seven percent of the African American population and is about as common as the trait for sickle cell anaemia.

The findings, which were generated in mice, could help identify at-risk individuals who might be able to tip the scales back in their favour by eating better and exercising more.

“This is one of the first examples of a susceptibility gene that would only be manifested through a modern lifestyle,” said Vann Bennett, M.D., Ph.D., senior author of the study and George Barth Geller Professor of Biochemistry, Cell Biology, and Neurobiology at Duke University School of Medicine. “The obesity epidemic really took off in the 1980’s, when sugary sodas and French fries became popular. It’s not like we suddenly changed genetically in 1980, but rather we have carried susceptibility genes that were exacerbated by this new diet. We think our findings are just the beginning, and that there are going to be many genes like this.’

Bennett, who is also an investigator with the Howard Hughes Medical Institute, discovered ankyrin-B more than thirty years ago. He found that ankyrin-B acts as a kind of protein anchor, tethering important proteins to the inside of the cell’s plasma membrane. Since his initial discovery, Bennett and other researchers have implicated defects in ankyrin-B in a wide variety of human afflictions, including irregular heartbeat, autism, muscular dystrophy, aging, and, more recently, diabetes.

Diabetes is quickly becoming one of the greatest threats to public health, as waistlines expand around the world and here in the United States. If the current trends continue, one in three Americans will have diabetes by 2050. Patients with type 1 diabetes do not make enough insulin, the hormone that helps process the glucose that builds up in the bloodstream after a meal. Patients with type 2 diabetes, the form linked to obesity, make insulin but become resistant to its effects.

Several years ago, the Bennett laboratory found evidence that ankyrin-B mutations might play a role in insulin secretion and metabolism. Since then, several studies have uncovered rare ankyrin-B variants that are associated with type 2 diabetes. One mutation, called R1788W, was more common in Caucasians and Hispanics. Another, called L1622I, was found exclusively in African-Americans, a group known to be at a particularly high risk of diabetes. But it was still unclear how these changes in the genetic code could set a course for diabetes.

To get at that answer, Bennett’s MD/PhD student Jane Healy created mouse models that carried these same human genetic variants. She and her colleagues found that animals with two copies of the R1788W mutation made less insulin than normal mice. Despite this shortcoming, their blood glucose levels were normal. So the researchers performed the rodent equivalent of a glucose tolerance test –- commonly used to screen for type 2 diabetes in people — to determine how quickly glucose was cleared from the bloodstream in the mutant mice. To their surprise, the mutant mice metabolized glucose more quickly than normal mice.

“We thought that the main problem in these mice would be with the beta cells that produced and secreted insulin,’ said Healy, co-author of the study and a former trainee in Bennett’s laboratory. “Instead, our most significant finding lay with the target cells, which took up much more glucose than expected.”

Glucose doesn’t enter cells and tissues all on its own, but instead has to rely on a second molecule, called GLUT4 transporter, to gain access. Normally, GLUT4 hangs out in the cell, like a hostess waiting for party guests to arrive. When insulin is present it acts as a kind of doorbell, alerting GLUT4 to spring into action and open the door to let glucose into the cell. When insulin goes away, the GLUT4 transporters close the door, turn around, and go back into the middle of the cell.

However, postdoctoral fellow Damaris Lorenzo, Ph.D., found that wasn’t the case with the mutant mice. After conducting a number of biochemistry experiments, Lorenzo ddiscovered that the mice had lots of GLUT4 on the surface of their muscle and fat cells even when there wasn’t any insulin around. That meant that glucose could flow in without necessarily having to bother with the doorbell.

This open door policy was an advantage when they were young, because it protected the animals from low insulin levels. But when the mice got older — or switched to a particularly high-fat diet — it made the mice fatter and, eventually, led them to become insulin resistant.

The researchers believe that long ago, the R1788W mutation — and the milder L1622I mutation — may have provided an evolutionary advantage. Aging hunter-gatherer types, who weren’t as effective at chasing down their next meal, needed to gain as much fat as possible to avoid starvation. Now that high-fat, high-calorie foods are plentiful in much of the world, these variants put people at increased risk for modern afflictions like obesity and diabetes. Duke University