By comparing gene expression patterns in cells that were sensitive (greater than 90 percent death) or resistant in response to tamoxifen, the group identified a suite of genes that failed to respond to the drug. Encouragingly, these genes were found only in the resistant cells. Furthermore, the team correlated their cell studies back to the clinic, finding a drug resistance signature that predicted the early relapse of breast cancer for women taking tamoxifen in two different clinical cohorts.

The team identified more than 30 kinases that repeated allowed the sensitive cells to grow in the presence of drug. Several were already known, but many were novel.

One of these, an atypical kinase called HSPB8, represents an entirely new mechanism for drug resistance. HSPB8 appears to confer resistance by the surprising mechanism of blocking autophagy, a process where cells escape death by consuming proteins inside the cell. This may suggest an important role for autophagy in developing resistance to tamoxifen.

"Women who had elevated levels of HSBP8 in one of our clinical cohorts, did worse on tamoxifen than women who did not," said LaBaer. "One gene alone in that cohort predicted outcome, which is very interesting. Relatively little is known about HSBP8 and so we have a gene with new territory to study."

Next, the team will investigate the role of several of the other genes identified in the study, in the hopes of contributing toward society's understanding of the underlying mechanisms of tamoxifen resistance in breast cancer. "We will continue to use this approach as a model of what happens in women, and looking from the perspective of what genes encourage resistance. If you can find these, you can identify drugs that inhibit them," said LaBaer.

Source: Arizona State University