2 min readMechanism that Explains Control of Cell Metabolism in Patient Response to Breast Cancer Drugs Discovered
La Jolla, CA — A new research study has discovered a mechanism that explains why some breast cancer tumours respond to specific chemotherapies and others do not.
The findings highlight the level of glutamine, an essential nutrient for cancer development, as a determinant of breast cancer response to select anticancer therapies, and identify a marker associated with glutamine uptake, for potential prognosis and stratification of breast cancer therapy. The study results were published online in Cancer Cell.
“Our study indicates that a protein called RNF5 determines breast cancer response to paclitaxel, one of the most common chemotherapy drugs,” said Dr. Ze’ev Ronai, scientific director of Sanford-Burnham’s La Jolla campus. “Paclitaxel belongs to a class of drugs called taxanes that work by triggering a stress response in cells that in turn promotes an interaction between RNF5 and glutamine uptake proteins. We found that this interaction causes degradation of the glutamine carrier proteins, leading to an insufficient supply of glutamine and the sensitization of breast cancer tumours to death.”
For some time researchers have known that many tumour cell types are dependent on glutamine for growth and survival, but didn’t know how glutamine uptake was regulated. The new findings demonstrate the importance of RNF5 in the control of glutamine uptake, and in antagonizing tumour development. The findings also suggest that testing tumours for RNF5 and glutamine carrier protein levels, such as SLC1A5, may be used to identify patients best suited to taxanes-based therapy.
“Not all tumours are equipped to respond to paclitaxel therapy,” said Ronai. “Using a cohort of more than 500 breast cancer patient samples, we found that only 30 percent of tumours exhibit high levels of RNF5 and low levels of glutamine carrier proteins—the optimal profile for response to paclitaxel.”
“Understanding these types of cell mechanisms and tumour characteristics that determine the response to anticancer drugs can lead to better patient stratification as well as improved therapy approaches,” said Dr. Gordon Mills, chairman of the Department of Systems Biology at MD Anderson Cancer Center, 2013 recipient of the Susan B. Komen Brinker Award for contributions to breast cancer research, and co-author of the study. “The opportunity to identify and target key pathways involved in the behaviour of breast cancer cells has the potential to both increase efficacy and decrease toxicity of therapy.”
“We also used this patient cohort to test the predictive value of measuring levels of glutamine carrier proteins as a prognostic marker. Our results indicate that these proteins are an outstanding marker of patient outcome, as good as currently used markers. We have started screening for inhibitors of glutamine carrier proteins as a potential new target for breast cancer treatment,” said Ronai, who is also examining the mechanism for glutamine control in other tumour types.
Article adapted from a Sanford-Burnham Medical Research Institute news release.
Publication: Regulation of Glutamine Carrier Proteins by RNF5 Determines Breast Cancer Response to ER Stress-Inducing Chemotherapies. Young Joo Jeon et al. Cancer Cell (2015): Click here to view.