Biomarkers which could help to predict resistance to chemotherapy in breast cancer patients have been identified by researchers from the University of Hull.
The researchers found a family of proteins to be twice as prevalent in clinical samples obtained from breast cancer patients who were resistant to chemotherapy than those who were successfully treated.
Chemotherapy resistance is a major problem for some types of breast cancer and many patients undergo treatment that does not work, delaying other more suitable treatments and subjecting the patient to adverse side effects in the process.
The Hull research identifies a number of potential biomarkers associated with resistance to common chemotherapy drugs, including epirubicin and docetaxel.
Lead researcher Dr Lynn Cawkwell, says: ‘A major goal in cancer research is to be able to predict the response of a patient to chemotherapy. Unfortunately, a reliable test has not yet been developed to achieve this. We hope our work can help to bring us a step closer.
‘Most of my work uses clinical samples instead of cell lines, thanks to the links I have with oncologists and surgeons at Castle Hill Hospital in Hull. Studying clinical samples gives a more accurate representation of what is relevant in real-life diseases.’
The project used two high-throughput processes to screen clinical samples of breast tumour tissue.
One screening method using antibodies identified 38 proteins that were twice as prevalent in samples from patients who were resistant to chemotherapy than those who were successfully treated. The other screening method used mass spectrometry and uncovered 57 potential biomarkers of which five belong to the 14-3-3 protein family.
The findings from both screening methods highlight the possible importance of proteins from the 14-3-3 family and their potential for development into a predictive test for clinical use. Dr Cawkwell’s team hope to investigate the protein family’s role more fully in chemotherapy resistance.
‘If we’re correct, we hope that by testing for these proteins, doctors will be able to anticipate a patient’s response to different chemotherapies, and decide which course of treatment is most appropriate for them.’
Dr Cawkwell’s team is continuing with this study, as well as investigating radiotherapy resistance in a number of different cancers. University of Hull

Resistances to drugs are the main reason why breast cancer cannot effectively be fought in many patients. Scientists from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) have now succeeded in restoring the sensitivity of resistant breast cancer cells to tamoxifen using a tiny RNA molecule. These snippets of RNA repress production of a protein that enhances cancer growth. In tissue samples of breast tumours, the investigators found clues that they also play a clinically relevant role.
Many breast cancer patients are treated with a drug called tamoxifen. The substance blocks the effect of oestrogen and thus suppresses the growth signals of this hormone in cancer cells. When resistance to the drug develops, tumour cells change their growth program: They change their behaviour and shape, become more mobile and also adopt the ability to invade surrounding tissue. Scientists working with PD (Associate Professor) Dr. Stefan Wiemann of the German Cancer Research Center (DKFZ) have now also observed these changes in tamoxifen resistant breast cancer cells.
‘Resistances to drugs are the main reason why therapies fail and disease progresses in many cancers,’ Wiemann explains. ‘We want to understand what goes on in the cells when this happens so we can develop better therapies in the future.’ Wiemann’s co-worker, Dr. Özgür Sahin, suspects that tiny pieces of RNA known as microRNAs play a role in resistance development. ‘These minuscule RNA snippets control many cellular processes by attaching themselves to target gene transcripts and thus repressing protein production.’
By treating breast cancer cells in vitro with regular doses of tamoxifen, Sahin’s team induced resistance of these cells to the drug. As resistance developed, the cancer cells switched to the development program that makes them grow even more invasively and more malignantly. Checking the complete spectrum of microRNAs in the resistant tumour cells, the investigators noticed that production of microRNA 375 was more strongly reduced than others. When they boosted the production of microRNA 375, the cells started responding again to tamoxifen and switched back to their normal growth program. ‘This strongly suggests that a lack of microRNA 375 both increases malignancy and contributes to resistance development,’ says Özgür Sahin.
If microRNA 375 levels are low, breast cancer cells increase the production of metadherin. Apparently, microRNA 375 suppresses the production of this cancer-promoting protein in healthy cells. In patients receiving tamoxifen therapy the team found that high metadherin levels in the cancer cells go along with a high risk of recurrence. This suggests that microRNA 375 and metadherin are involved in the development of resistance to tamoxifen.
‘The analysis of microRNAs in breast cancer has put us on the track of metadherin. We will possibly be able to specifically influence the cancer-promoting properties of this protein in the future,’ says Wiemann describing the goal of further research. The German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ)

Scientists behind Olympic Team GB are working on genetic tests to understand why some athletes are prone to injury, BBC’s Newsnight has learned.
Tendon injuries and stress fractures are common in elite athletes, but how and why they happen is less clear.
University College London’s Prof Hugh Montgomery says they have found a gene they think strongly influences the risk of stress fracture and more will come.
It is hoped the research will allow training to be individually tailored.
Diet, repetitive strain and loading are all known to play a part, and scientists say there is clearly a strong genetic element.
Director of the Institute for Human Health and Performance at University College London, Prof Montgomery carried out groundbreaking work on genes and fitness in the 1990s, most notably the ‘ACE’ gene, thought to be linked to endurance.
‘If we understood that genetic component we would have a much better understanding of the patho-physiology – the disease processes that let that happen,’ says Prof Montgomery.
He has been working closely with the English Institute of Sport (EIS), which aims to apply the latest in sports science and medicine for the benefit of Britain’s Olympic and Paralympic athletes.
EIS’s Director of Sport Science, Dr Ken van Someren, told Newsnight he is keen to apply the latest genetics discoveries.
‘If we can identify some particular genes that are associated with a higher risk of injury in certain individuals, and we think we’re close, we can tailor the training, conditioning and preparation that we put those individuals through.’
He added that should injury occur, the research could also influence the medical treatment the person receives.
But Dr van Someren stressed that there is no intention to use genes as a means of identifying sporting talent.
He says that for many people sport is about a fun and healthy lifestyle and genetics should not be used to screen people in or out of sport, adding that although genes might tell us a lot about the likelihood or probability of success, it is not an absolute science and there would be a danger of ‘missing out on some future champions.’
Prof Montgomery believes that looking for tomorrow’s sporting champions should involve looking at a combination of genes and the environment, rather than just relying on screening the genome.
He says we should look a person’s performance and dedication and to the sport rather than trying to ‘predict that dedication and performance by gene screening.’ BBC

Chronic kidney disease is associated with a higher risk of kidney and urothelial cancer, but not other types of cancer, according to research being presented at the American Society of Clinical Oncology’s Genitourinary Cancers Symposium in San Francisco. Urothelial cancers affect the bladder, ureters, and renal pelvis.
Researchers from Huntsman Cancer Institute at the University of Utah and Kaiser Permanente’s Northern California Division of Research found that higher risk for kidney cancer and urothelial cancer is associated specifically with chronic kidney disease as measured by a reduced flow rate of filtered fluid through the kidneys. The researchers found no significant associations with prostate, colorectal, lung, breast, or any other cancers.
‘We’ve known for some time that the incidence of chronic kidney disease continues to rise and that an estimated 11.5 percent of the United States population has reduced kidney function,’ said William T. Lowrance, MD, with Huntsman Cancer Institute and lead author of the research. ‘We also know from previous research that there are higher risks of cancer in people with end-stage renal disease requiring dialysis or transplantation.’
‘What we haven’t known is whether less severe kidney disease is independently associated with cancer,’ said Alan S. Go, acting director of the Kaiser Permanente Division of Research, and the senior author of the abstract being presented this week. ‘These findings describe an association that could have important public health implications for screening and early detection of cancer in the growing number of patients with chronic kidney disease.’
Researchers evaluated the association between chronic kidney disease and the risk of incident cancer in a large, diverse, community-based population linked to a regional cancer registry. As was hypothesised, they found an independent, graded increased risk of kidney cancer with lower estimated glomerular filtration rate, the flow rate at which the kidneys filter fluid. The study examined all people with measured kidney function who are receiving care within Kaiser Permanente Northern California, a large, integrated health care delivery system providing care to 3.2 million members. The Kaiser Permanente Cancer Registry links to the National Cancer Institute-sponsored Surveillance, Epidemiology, and End Results (SEER) Cancer Registry that collects detailed data on incident cancer site, initial treatment and other patient characteristics.
Research scientists adjusted for a large set of factors that may confound the relationship between level of kidney function and cancer risk. The risk of renal cancer retained a robust and graded association with renal function. As chronic kidney disease worsened, the risk of renal cancer increased, they explained. There was a similar association between estimated GFR and urinary tract (excluding prostate) cancer, although the magnitude of this association was less pronounced than observed with renal cancer, they added. Kaiser Permanent

New research, presented at the 54th Annual Meeting of the American Society of Hematology (ASH), has identified important associations between Plasmodium falciparum (Pf) malaria and endemic Burkitt Lymphoma (eBL) that may help researchers identify young children who are more susceptible to eBL.
Unlike previous studies in which malaria infection alone was considered the important factor, this study approached the evolving complexity and heterogeneity of the humoral immune response to Pf as a key component for risk of developing eBL in young children who reside in malaria endemic areas of Equatorial Africa. The circumstances potentially set the stage for the development of serological signatures as biomarkers to better indicate the risk of developing eBL during malaria infection.
The study, titled ‘Risk of Burkitt Lymphoma Correlates with Breadth and Strength of Antibody Response to Plasmodium falciparum Malaria Stage-Specific Antigens,’ was authored by Jeffrey Bethony, Ph.D., associate professor in the department of microbiology, immunology, and tropical medicine (MITM) at the George Washington University (GW) School of Medicine and Health Sciences (SMHS), along with Amar Jariwala, M.D., assistant research professor in the department of MITM at GW SMHS, and Maria Candida Vila, graduate student at the GW SMHS Institute for Biomedical Sciences. This research was done in collaboration with Sam Mbulaiteye, M.D., infections and immunoepidemiology branch, division of cancer epidemiology and genetics, National Cancer Institute, National Institutes of Health, who spent decades collecting the case and control sera in Ghana, as well as the study design and statistics.
The GW SMHS research team developed, optimised, and standardised an extensive panel of serological tests of recombinant Pf antigens representing several stages of the parasite life-cycle assayed in more than 700 cases and control samples from young children. These young children were either resident in Pf malaria endemic areas of Ghana, had eBL, or were the same age, sex, and of the same village to match a child who did not have eBL. Bethony and his colleagues used an immunomics approach to their antibody response to Pf malaria. This enabled different statistical and epidemiological associations to be made between a range of antibody response to Pf malaria antigens and eBL, establishing a pattern of immune responses rather than a single immune response, identifying the children who are at risk for developing eBL.
‘Plasmodium falciparum malaria has long been suspected as an important trigger to Epstein Barr Virus associated lymphoma of very young children living in Equatorial Africa,’ said Bethony. ‘Our study adds to this literature, explaining that it is not simply the presence or absence of Pf malaria infection, but the breath and complexity of the antibody response to malaria that may be the true indicating factor for who develops eBL and who does not.’
The study showed a significant increase in the risk of developing eBL in young children who had a distinct pattern of antibody responses to several different recombinant Pf malaria antigens, including some antigens which are vaccine candidates. Of special note, the study also found a significant decreased risk of eBL in children with antibodies to SE36, a vaccine candidate protein that has been associated with lower risk of malaria in epidemiological studies.
These results not only confirm a strong association between Pf malaria and eBL, but provide a new perspective on the long established relationship between Pf malaria and eBL. This could pave the way for future studies that use protein arrays, containing hundreds of recombinant proteins to develop an antibody signature for children most at risk of developing eBL during Pf malaria infection. George Washington University