Genes that cause drug resistance and aggressiveness in breast cancer identified

Dutch researchers have identified a novel set of seven genes that causes drug resistance and aggressiveness in the most common form of breast cancer, and may act as therapeutic targets for personalized treatment and prevention of breast cancer.

The researchers stated that these genes are found in estrogen receptor-positive (ER+) breast cancer, which is usually more treatable than breast cancer that is not triggered by estrogen.

Most of the human breast tumors are ER+ and respond to anti-estrogen therapy, such as tamoxifen, but in advanced disease, only half of ER+ breast cancer is initially sensitive to tamoxifen, and in the majority of those patients, it becomes resistant to drug therapy.

Researchers at Erasmus Medical Center in Rotterdam hypothesized that cell proliferation in the absence of estrogen and in the presence of tamoxifen would be regulated at a molecular level by specific genes.

In order to identify these genes involved in cell growth, they used a functional screen based on insertion mutagenesis with mouse retroviruses.

They succeeded in finding some of the seven genes and included them in a new family dubbed "Breast Cancer Anti-estrogen Resistance" (BCAR), which are already linked with cancer development in general. Some of the seven (AKT1, AKT2, BCAR1, BCAR3, EGFR, GRB7, and TRERF1) had been linked to resistance to tamoxifen.

"We set out to define the molecular mechanisms underlying anti-estrogen resistance and this provided a collection of BCAR genes which are representative of the escape pathways that these breast cancer cells take in our laboratory studies," said the study's lead investigator, Lambert Dorssers, Ph.D., a cell biologist at the Department of Pathology of the Erasmus Medical Center, in Rotterdam.

"We have also shown that the majority of the BCAR genes identified are linked to clinical breast cancer, suggesting that their signaling pathways contribute to the progression of breast cancer and to tamoxifen therapy resistance," he added.

Using the functional screen, the investigators examined surgically removed primary tumors from 413 patients who had not yet received systemic therapy and found three genes - AKT2, EGFR, and TRERF1 - that were independently associated with tumor aggressiveness.

In addition, other studies of breast tumor samples from recurrent patients treated with tamoxifen, had found five genes - BCAR3, ERBB2, GRB7, TLE3, and TRERF1 - that were associated with progression-free survival, depending on the level of their expression. Some of these genes were confirmed by the current study.

Expression of the genes could also be used to "classify patients for more intensive or alternative adjuvant treatment, or to suggest specific treatments in the advanced state of ER-positive disease," said Dorssers. (ANI)

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