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Genetic biomarker predicted tamoxifen resistance in ER-positive breast cancer
Loss of function in the deubiquitinase USP9X appears to be associated with resistance to tamoxifen in patients with ER alpha-positive breast cancer, according to study findings.
The results suggest this gene signature may help predict how patients will respond to the drug, researchers wrote.
Rene Bernards
“About one-third of women with hormone receptor-positive breast cancer experience a relapse after adjuvant treatment with tamoxifen,” Rene Bernards, PhD, head of the division of molecular carcinogenesis at Netherlands Cancer Institute in Amsterdam, said in a press release. “Median overall survival in these patients, even with further treatment, is around 30 to 45 months. It has been very difficult to identify patients whose tumors lack a proper response to tamoxifen, the most frequently used drug in breast cancer.”
To determine whether an association existed between tamoxifen resistance and loss of function of certain genes, Bernards and colleagues conducted a large-scale genetic screen of loss of function in ZR-75-1 luminal breast cancer cells.
Based on this screen, researchers were able to isolate a gene called USP9X, and they determined loss of function of this gene in breast cancer cells resulted in tamoxifen resistance.
The researchers then attempted to identify other genes that were altered during tamoxifen treatment in the absence of USP9X. They used publicly available data sets to analyze gene expression in 680 patients who underwent postoperative tamoxifen treatment and had known treatment outcomes.
“Using a gene signature defined by their differential expression after USP9X attenuation in the presence of tamoxifen, we were able to define patients with ER alpha-positive breast cancer experiencing a poor outcome after adjuvant treatment with tamoxifen,” Bernards and colleagues wrote.
Researchers determined the signature was unable to predict outcomes in patients who were not treated with tamoxifen.
“We have used a very innovative approach to identify genes that help foretell whether a patient will respond to tamoxifen, and we showed that this gene signature performed well in two large patient groups,” Bernards said. “We were able to translate results from cell culture experiments into a diagnostic tool that has the potential to help identify breast cancer patients that will benefit from tamoxifen.”
Disclosure: The researchers report no relevant disclosures.