Identification Of BCAR Genes Relevant For Breast Cancer Progression And Endocrine Therapy Resistance

These genes, some of which are novel, could provide therapeutic targets for personalized treatment of breast cancer and, possibly, for prevention of disease, they say.

These genes are found in estrogen receptor-positive (ER+) breast cancer, which investigators say is usually more treatable than breast cancer that is not fueled by estrogen. The majority of human breast tumors are ER+ and most 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, the disease eventually becomes resistant to drug therapy. Understanding the molecular basis of this drug resistance was the focus of the Dutch study.

A research team from 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. To identify these genes involved in cell growth, they used a functional screen based on insertion mutagenesis with mouse retroviruses. This unique approach in human solid tumor cells took more than a decade of painstaking work.

Some of the seven genes the researchers found -- which they have included in a new family dubbed "Breast Cancer Anti-estrogen Resistance" (BCAR) -- are already associated with cancer development in general but others are novel. Few 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 said.

Using the functional screen, the investigators looked at 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 other studies of breast tumor samples from recurrent patients treated with tamoxifen, they 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. "For example, we found that high levels of GRB7 are associated with a quicker relapse," Dorssers said.

The researchers are now defining how these genes function within breast cancer cells in order to pinpoint possible targets for treatment. 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," he said.

This research was presented at the American Association for Cancer Research 2008 Annual Meeting, April 12-16.