The study by lead author Justin Balko, Pharm.D., Ph.D., was published online June 10, 2012 in Nature Medicine in advance of print publication. Balko is a postdoctoral fellow in the laboratory of Carlos L. Arteaga, M.D., associate director for Clinical Research and director of the Breast Cancer Program at VICC, who led the study.
About 30 percent of breast cancer patients have a pathological complete response when chemotherapy is used to shrink tumors prior to surgery. However, many patients still have residual cancer in the breast after neoadjuvant chemotherapy (NAC) is completed. These patients are at a higher risk of cancer recurrence and death.
The investigators suspected that profiling tumors after neoadjuvant chemotherapy would identify genes associated with resistance to this form of treatment. They studied gene expression patterns in 49 breast tumors obtained during surgery after four months of NAC.
They identified and analyzed specific groups of genes associated with high-grade, chemotherapy-resistant tumors, labeling their 244 unique genes the CLUSTER signature, and combined this panel with previously identified gene signatures to search for distinctive patterns of behavior.
The investigators found that low concentrations of dual specificity protein phosphatase 4 (DUSP4) is strongly correlated with faster tumor cell growth following neoadjuvant chemotherapy. Low DUSP4 was also correlated with a type of breast cancer known as basal-like breast cancer (BLBC). DUSP4 promoter methylation and gene expression patterns of Ras-ERK pathway activation were also higher in BLBC relative to other breast cancer subtypes.
When DUSP4 was present, chemotherapy was effective against cancer cells, whereas when DUSP4 was experimentally deleted, there was a much lower response to chemotherapy.
"These data suggest that cells with low DUSP4 expression are enriched during NAC and that low DUSP4 expression in residual resected breast tumors is a potential biomarker for drug resistance and a high likelihood of tumor recurrence," said Balko.
The group also hypothesized that DUSP4 may be a potential biomarker for response to drugs that inhibit the MEK kinase. Using DUSP4-deficient tumors established in mice, they compared treatment with the chemotherapy drug docetaxel, with and without the MEK inhibitor selumetinib. This study showed that the combination was much more effective than docetaxel alone at eliminating the mouse tumors.
"These data support exploratory clinical trials combining chemotherapy and MEK inhibitors in patients with DUSP-deficient basal-like breast cancer," said Balko.
VICC investigators involved with the study include Rebecca Cook, Ph.D., David Vaught, Ph.D., María Gabriela Kuba, M.D., Todd Miller, Ph.D., Neil Bhola, Ph.D., Melinda Sanders, M.D., Nara Granja-Ingram M.D., J. Joshua Smith, M.D., Ph.D., and Ingrid Meszoely, M.D. Other investigators include Janine Salter, M.S., and Mitch Dowsett, Ph.D., at the Royal Marsden Hospital in London, UK; Katherine Stemke-Hale, Ph.D., Ana María González-Angulo, M.D., M.Sc., and Gordon Mills, M.D., Ph.D., at the MD Anderson Cancer Center in Houston, Texas; Joseph Pinto, M.S., and Henry Gόmez, M.D., at the Instituto Nacional de Enfermedades Neoplásicas (INEN) in Lima, Perú.
This work was supported by funding from the National Institutes of Health (NIH) through National Cancer Institute (NCI) Breast Cancer Specialized Program of Research Excellence (SPORE) Grant P50CA98131 and Vanderbilt-Ingram Cancer Center Support Grant P30CA68485. Other funding was provided by the Breast Cancer Research Foundation, the American Cancer Society, the Lee Jeans Translational Breast Cancer Research Program, and a Stand Up to Cancer/American Association for Cancer Research (SU2C/AACR) Dream Team award.
Dagny Stuart | EurekAlert!
Drone vs. truck deliveries: Which create less carbon pollution?
31.05.2017 | University of Washington
New study: How does Europe become a leading player for software and IT services?
03.04.2017 | Fraunhofer-Institut für System- und Innovationsforschung (ISI)
An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.
Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...
Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.
Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...
Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.
As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...
Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.
With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...
Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine
Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...
19.06.2017 | Event News
13.06.2017 | Event News
13.06.2017 | Event News
23.06.2017 | Physics and Astronomy
23.06.2017 | Physics and Astronomy
23.06.2017 | Information Technology