Molecular hallmarks of breast cancer sensitivity to ErbB2-targeted therapies

Many breast tumors are driven by a protein ErbB2 which they overproduce. These tumors are treated with drugs called ErbB2 inhibitors but not everyone benefits from them. The drugs can damage the heart and are costly. Hence, predicting who can and who cannot benefit from these drugs would be of great value. Breast tumor cells originate from normal breast cells forming a layer in the breast. Normal cells die when they detach from this layer. ErbB2 blocks death of cancer cells after they detach, and this allows them to form tumors and spread through the body. How ErbB2 causes these effects is not well understood. We have found that ErbB2 triggers signals causing loss of a protein Irf6 in tumor cells detached from their normal location and that Irf6 loss reduces cellular amount of a cell death-inducing protein Perp. Cells lacking Perp do not die outside of their normal location. We have also noticed that ErbB2 inhibitors increase Irf6 and Perp levels in detached tumor cells that are sensitive to these medicines but not in the cells resistant to the drugs. We will examine what signals ErbB2 induces to cause Irf6 and Perp loss in breast tumor cells and whether this loss allows the cells to form tumors and spread through the body. Some ErbB2-overproducing tumors are treated with ErbB2 inhibitors in an effort to shrink the tumor which is then surgically removed. The patient further receives these drugs to kill tumor cells that may have stayed in the body. We will test human breast tumor samples obtained before and after treatment with the drugs to assess whether the increase in Irf6 and Perp levels in the tumor after it is forced to shrink by the drugs predicts whether the patient will benefit from these medicines. This will allow the patients that are not expected to benefit from the drugs to avoid them after the surgery. Thus we expect that our work will uncover a new breast cancer mechanism and help doctors decide which patients can benefit from ErbB2 inhibitors.