Study identifies genes linked to resistance to breast cancer chemotherapy

June 11, 2012, Vanderbilt University Medical Center

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 Program at VICC, who led the study.

About 30 percent of 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 (NAC) is completed. These patients are at a higher risk of 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 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 of Ras-ERK pathway activation were also higher in BLBC relative to other breast cancer subtypes.

When DUSP4 was present, chemotherapy was effective against , 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 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.

Explore further: Genetic predictor of breast cancer response to chemotherapy

Related Stories

Genetic predictor of breast cancer response to chemotherapy

May 10, 2012
Chemotherapy is a major first line defense against breast cancer. However a patient's response is often variable and unpredictable. A study published in BioMed Central's open access journal BMC Medical Genomics shows that ...

Immune-response genes affecting breast tumor eradication

May 3, 2012
Breast cancer patients whose tumors express high levels of genes related to immune response are more likely to have their tumor completely eradicated by pre-operative chemotherapy compared to patients with low expression ...

Chemotherapy is as effective before breast cancer surgery as after

September 8, 2011
Whether chemotherapy is given before or after breast-conserving therapy (BCT) does not have an impact on long-term local-regional outcomes, suggesting treatment success is due more to biologic factors than chemotherapy timing, ...

Breast MRI helps predict chemotherapy's effectiveness

May 23, 2012
Magnetic resonance imaging (MRI) provides an indication of a breast tumor's response to pre-surgical chemotherapy significantly earlier than possible through clinical examination, according to a new study published online ...

Recommended for you

Dulling cancer therapy's double-edged sword

January 17, 2018
Researchers have discovered that killing cancer cells can actually have the unintended effect of fueling the proliferation of residual, living cancer cells, ultimately leading to aggressive tumor progression.

Researchers develop swallowable test to detect pre-cancerous Barrett's esophagus

January 17, 2018
Investigators at Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center have developed a simple, swallowable test for early detection of Barrett's esophagus that offers promise ...

Scientists zoom in to watch DNA code being read

January 17, 2018
Scientists have unveiled incredible images of how the DNA code is read and interpreted—revealing new detail about one of the fundamental processes of life.

T-cells engineered to outsmart tumors induce clinical responses in relapsed Hodgkin lymphoma

January 16, 2018
WASHINGTON-(Jan. 16, 2018)-Tumors have come up with ingenious strategies that enable them to evade detection and destruction by the immune system. So, a research team that includes Children's National Health System clinician-researchers ...

Researchers identify new treatment target for melanoma

January 16, 2018
Researchers in the Perelman School of Medicine at the University of Pennsylvania have identified a new therapeutic target for the treatment of melanoma. For decades, research has associated female sex and a history of previous ...

More evidence of link between severe gum disease and cancer risk

January 16, 2018
Data collected during a long-term health study provides additional evidence for a link between increased risk of cancer in individuals with advanced gum disease, according to a new collaborative study led by epidemiologists ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.