Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Vanderbilt-led study identifies genes linked to resistance to breast cancer chemotherapy

12.06.2012
A study led by Vanderbilt-Ingram Cancer Center (VICC) investigators has identified a gene expression pattern that may explain why chemotherapy prior to surgery isn't effective against some tumors and suggests new therapy options for patients with specific subtypes of breast cancer.

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!
Further information:
http://www.vanderbilt.edu

Further reports about: BLBC Cancer MEK VICC breast breast cancer breast tumors potential biomarker

More articles from Studies and Analyses:

nachricht Rutgers-led innovation could spur faster, cheaper, nano-based manufacturing
14.02.2018 | Rutgers University

nachricht New study from the University of Halle: How climate change alters plant growth
12.01.2018 | Martin-Luther-Universität Halle-Wittenberg

All articles from Studies and Analyses >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Attoseconds break into atomic interior

A newly developed laser technology has enabled physicists in the Laboratory for Attosecond Physics (jointly run by LMU Munich and the Max Planck Institute of Quantum Optics) to generate attosecond bursts of high-energy photons of unprecedented intensity. This has made it possible to observe the interaction of multiple photons in a single such pulse with electrons in the inner orbital shell of an atom.

In order to observe the ultrafast electron motion in the inner shells of atoms with short light pulses, the pulses must not only be ultrashort, but very...

Im Focus: Good vibrations feel the force

A group of researchers led by Andrea Cavalleri at the Max Planck Institute for Structure and Dynamics of Matter (MPSD) in Hamburg has demonstrated a new method enabling precise measurements of the interatomic forces that hold crystalline solids together. The paper Probing the Interatomic Potential of Solids by Strong-Field Nonlinear Phononics, published online in Nature, explains how a terahertz-frequency laser pulse can drive very large deformations of the crystal.

By measuring the highly unusual atomic trajectories under extreme electromagnetic transients, the MPSD group could reconstruct how rigid the atomic bonds are...

Im Focus: Developing reliable quantum computers

International research team makes important step on the path to solving certification problems

Quantum computers may one day solve algorithmic problems which even the biggest supercomputers today can’t manage. But how do you test a quantum computer to...

Im Focus: In best circles: First integrated circuit from self-assembled polymer

For the first time, a team of researchers at the Max-Planck Institute (MPI) for Polymer Research in Mainz, Germany, has succeeded in making an integrated circuit (IC) from just a monolayer of a semiconducting polymer via a bottom-up, self-assembly approach.

In the self-assembly process, the semiconducting polymer arranges itself into an ordered monolayer in a transistor. The transistors are binary switches used...

Im Focus: Demonstration of a single molecule piezoelectric effect

Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale

Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

2nd International Conference on High Temperature Shape Memory Alloys (HTSMAs)

15.02.2018 | Event News

Aachen DC Grid Summit 2018

13.02.2018 | Event News

How Global Climate Policy Can Learn from the Energy Transition

12.02.2018 | Event News

 
Latest News

Basque researchers turn light upside down

23.02.2018 | Physics and Astronomy

Finnish research group discovers a new immune system regulator

23.02.2018 | Health and Medicine

Attoseconds break into atomic interior

23.02.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>