UT Southwestern Medical Center scientists have identified a strong link between the most aggressive type of breast cancer and a gene that regulates the body’s natural cellular recycling process, called autophagy.

Based on analysis of two large breast cancer databases, reduced activity of an autophagy gene, beclin 1, was related to both a higher incidence of triple-negative breast cancer and a poorer prognosis for breast cancer patients.

The study is the first to document a correlation between beclin 1 and triple-negative human breast cancer and validates research in mouse models.

“We have potentially identified a new pathway to be targeted in the most aggressive, difficult-to-treat form of breast cancer,” said Dr. Beth Levine, Director of the Center for Autophagy Research and a Howard Hughes Medical Institute Investigator at UT Southwestern. “These data suggest that decreased beclin 1 activity contributes to breast cancer and poor survival outcomes. As a result, therapies that increase beclin 1 activity in breast cancer may be beneficial.”

Triple-negative breast cancer – which accounts for 10 to 20 percent of breast cancer – is called such because the cancer’s cells lack oestrogen and progesterone receptors and also do not have an excess of the human growth factor receptor 2 (HER2) protein on their surfaces. Chemotherapy, the standard treatment, has been limited in its effectiveness against triple-negative breast cancer.

 “With low beclin 1 expression, you have up to a 35-fold higher risk of having triple-negative breast cancer. That’s really strong,” said Dr. Levine, who holds the Charles Cameron Sprague Distinguished Chair in Biomedical Science and is co-senior author of the study with Dr. Yang Xie, Associate Professor of Clinical Science.

UT Southwestern researchers analysed 3,057 breast cancer cases for levels of expression of beclin 1 and BRCA1, a nearby gene that is associated with inherited breast cancer. The data came from The Cancer Genome Project in the United States (1,067 cases) and the Molecular Taxonomy of Breast Cancer International Symposium in the United Kingdom and Canada (1,992 cases).

“We know that about 35 percent of all breast cancers are missing copies of both the beclin 1 and BRCA1 genes,” said Dr. Levine. “To find out which of the two genes is important, we looked at the levels of expressions of both genes and how they related to different clinical features of breast cancer. Strong associations were seen between low expression of beclin 1, but not BRCA1, and adverse clinical features.”

Along with the 35-fold higher risk of having triple-negative breast cancer, the findings showed low levels of beclin 1 activity also correlated with worse outcomes.

“Patients with breast cancer and low beclin 1 expression had a 67 percent increase in the risk of dying from breast cancer compared with patients who had higher levels of beclin 1 expression,” Dr. Xie said.

Increasing beclin 1 activity could, therefore, become a new therapy for breast cancer patients, especially those with the triple-negative type. Several approved drugs that happen to increase beclin 1 activity are already used for other types of cancer. They included four classes of drugs: inhibitors of either beclin 1/BCL-2 binding, protein kinase B (AKT), epidermal growth factor receptor (EGFR), or HER2. UT Southwestern Medical Center

Researchers at the University of California, San Diego School of Medicine have, for the first time, clearly defined the epidemiology of gastrointestinal stromal tumours (GIST), which occur primarily in the lining of the stomach and small intestine. One key finding: Patients of Asian descent, who have not previously been identified as an at-risk population, are 1.5 times more likely than other patient groups to be diagnosed with this type of tumour.

 “Previous journal articles never clearly differentiated GIST from several other tumours, even though they have different biologies,” said Jason Sicklick, MD, assistant professor of surgery and a surgical oncologist at UC San Diego Health System. “This study more clearly identifies at-risk populations in the United States as well as incidence rates, survival trends and risk factors for the disease.”

Prior to 2001, GIST-specific histology codes were not used in medical coding, which meant that a variety of tumour types, such as leiomyoma and leiomyosarcoma, spindle cell, myofibroblastic, desmoid and KIT-positive metastatic melanomas were all lumped into one category. Sicklick and his team have used a new generation of precise pathologic diagnostic codes to better define the incidence and distribution of GIST among different patient groups.

The research team from UC San Diego Moores Cancer Center found that the overall incidence rate was 6.8 cases per million people and that the rate rose from 2001 to 2011. During the study period, the median age of GIST diagnosis was 64 years old. GISTs were more common in men.

“Contradicting prior reports we see a definite survival disparity, particularly among patients of African-American descent,” said Sicklick.

Persons of African-American or Asian/Pacific Islander descent were 2.1 and 1.5 times more likely to develop GIST than Caucasians, respectively.

“Further studies are needed to understand why these groups are at-risk as it could carry important diagnostic, prognostic and therapeutic implications throughout the United States,” said James Murphy, MD, assistant professor of radiation oncology at UC San Diego School of Medicine and a radiation oncologist at UC San Diego Health System. University of California – San Diego

Researchers at UT Southwestern Medical Center have identified hyaluronon (HA) as a critical substance made by the body that protects against premature births caused by infection. Pre-term birth from infection is the leading cause of infant mortality in many countries according to the World Health Organization. The findings of the study are the first to identify the specific role that HA plays in the reproductive tract.

Dr. Yucel Akgul, first author and senior author Dr. Mala Mahendroo
“We found that HA is required to allow the epithelial lining of the reproductive tract to serve as the first line of defence against bacterial infections,” said senior author Dr. Mala Mahendroo, an Associate Professor in the Department of Obstetrics and Gynecology’s Cecil H. and Ida Green Center for Reproductive Biology Sciences. “Because of this action, HA offers cervical protection against the bacterial infections that cause 25 to 40 percent of pre-term births in women.”

Hyaluronon is a natural substance found in many tissues, and is both a lubricant and a beneficial component of eyes, joints, and skin. It has long been thought to play an essential role in increasing the cervix’s flexibility during the birth process; however, the study, which was conducted using mouse models, showed that HA is not essential for increased cervical pliability during late pregnancy. Rather, the substance plays an important barrier role in epithelial cells of the lower reproductive tract and in so doing protects against infection-related pre-term birth. The World Health Organization estimates that 1.09 million children under age 5 die from direct complications of being born prematurely, meaning before the 37th week of pregnancy.

Previous studies by UT Southwestern reproductive biology researchers showed that HA is present in both the cervix and cervical mucus of pregnant women. Next steps include determining the mechanism by which HA affects cervical protection against infection.

“This study demonstrates that HA plays a crucial role in the epithelial barrier as well as the cervix’s mucus,” said Dr. Yucel Akgul, first author of the study and research scientist in the Department of Obstetrics and Gynecology. “Our next step is to identify exactly how HA protects the cervix, which can have important clinical implications in the effort to reduce infection-mediated pre-term labour.” UT Southmwestern Medical Center

A new genetic discovery in the field of Huntington’s disease (HD) could mean a more effective way in determining severity of this neurological disease when using specific treatments. This study may provide insight for treatments that would be effective in slowing down or postponing the death of neurons for people who carry the HD gene mutation, but who do not yet show symptoms of the disease.

The work was led by researchers at Boston University School of Medicine (BUSM) and currently appears in BMC Medical Genomics.

HD is a fatal, inherited neurological disease that usually manifests between 30 and 50 years of age. The disease is caused by a genetic defect that is passed from parent to child in the huntingtin gene. Having too many repeated elements in the gene sequence causes the disease and an increasing number of repeats leads to earlier onset and increased severity of the disease.

The researchers studied the brains of people who died from HD and those who died of other, non-neurological diseases and identified a very specific genetic signal that strongly correlates disease severity and extent of neuronal, or brain cell death. The genetic signal, also called a microRNA, silences certain genes in the DNA. Genes that lead to the toxic effects of the huntingtin gene may be silenced by these microRNAs, in particular the miR-10b-5p microRNA.

‘The findings that we found most interesting were the microRNAs that reflect the extent of the neuron death in the brain, since it is this process that causes the debilitating symptoms of the disease and eventually leads to the death of the individual,’ explained senior author Richard H. Myers, PhD, Director of the Genome Science Institute at BUSM.

According to the researchers these findings may represent a more effective way to tell whether or not HD treatments may be slowing down the pace of the death of brain cells. ‘If miR-10b-5p measurements can provide a faster and more effective way to determine whether or not a specific treatment is protecting brain neurons, it may be possible to study more potential treatments for HD more quickly. Equally importantly, it may become feasible to perform these trials in people who are HD gene carriers, but who do not yet show symptoms, by giving evidence for which trials may postpone onset and provide more healthy years of life,’ added Myers.

These findings also suggest that other microRNAs may also be important markers of severity for other neurological diseases such as Parkinson’s disease and Alzheimer’s disease. Further research is already being conducted in Parkinson’s Disease by Myers and his colleagues. EurekAlert

Tumour cells isolated from the blood of patients with triple negative breast cancer reveal similar cancer-driving mutations as those detected from standard biopsy, suggesting that circulating cells could one day replace tissue biopsies
The genetic fingerprint of a metastatic cancer is constantly changing, which means that the therapy that may have stopped a patient’s cancer growth today, won’t necessarily work tomorrow. Although doctors can continue to biopsy the cancer during the course of the treatment and send samples for genomic analysis, not all patients can receive repeat biopsies. Taking biopsies from metastatic cancer patients is an invasive procedure that it is frequently impossible due to the lack of accessible lesions.  Research suggest that tumour cells circulating in the blood of metastatic patients could give as accurate a genomic read-out as tumour biopsies.

“Counting the number of circulating tumour cells (CTCs) can tell us whether a patient’s cancer is aggressive, or whether it is stable and responding to therapy,” says the article’s first author Sandra V. Fernandez, Ph.D., assistant professor of Medical Oncology at Thomas Jefferson University. “Our work suggests that these cancer cells in the blood also accurately reflect the genetic status of the parent tumour or its metastases, potentially giving us a new and easy to source of genomic information to guide treatment.”

First discovered for their diagnostic potential in 2004, circulating tumour cells are beginning to be used in the clinic to help guide treatment decisions and track a patient’s progress as the cancer progresses. Although other studies have pooled the collected CTCs and compared their collective genetic signature to that of the primary tumour, this is the first study to look at the genomic signature of individual tumour cells in circulation. In order to isolate single tumour cells from the blood, the authors used a new technology, DEPArrayTM , in their laboratory.
The researchers compared tissue biopsies surgically removed from two patients with inflammatory breast cancer with circulating tumour cells (CTCs). Breast tissue samples from both patients showed a specific mutation in a region of a cancer-driving gene, p53. The authors studied this mutation in several CTCs isolated from both patients. They found that in several of the CTCs collected, the mutations matched with the tumour biopsy, however in one patient, some of circulating tumour cells had an additional mutation. “Since inflammatory breast cancer is a very rapidly changing disease, we think this additional mutation may have been acquired after the original surgical biopsy was taken,” said Dr. Fernandez. In the case where an additional p53 mutation was found, the blood to isolate CTCs were drawn one year later than the breast tissue biopsy was taken.
Although further work analyzing a greater number of genes and samples is needed, the work shows that CTCs offer the possibility of capturing the most current genomic information in an easy-to-obtain sample such as blood, thus helping guide treatment decisions. It also suggests that it may be necessary to test more than one cell for the most accurate reading, as the CTC population appears to be heterogenous. Thomas Jefferson University (TJU)