Author: Lauren M. Pferdehirt

Publisher:

Published: 2015

Total Pages: 246

ISBN-13:

Breast cancer is the most common cause of cancer-related death and is the most frequently diagnosed cancer in women worldwide. Mortality from breast cancer is principally due to tumor recurrence, which may be diagnosed up to 20 years after treatment of the primary tumor. Since relapse is a consequence of the persistence of residual tumor cells, identifying the mechanisms involved in tumor cell survival and escape from therapy is essential for the development of more effective strategies for improving patient outcomes. Using a genetically-engineered mouse model for breast cancer dormancy and recurrence, we now report that inhibition of HER2/neu signaling in primary tumors induces cellular senescence and that this process may serve as a barrier to tumor relapse. We find that the ETS-domain transcription factor Ehf is up-regulated following acute HER2/neu signaling inhibition and induces senescence in mouse mammary tumor cells. Notably, Ehf expression is lost in residual breast cancer cells that survive tumor regression, as well as in recurrent tumors. Analogous to its behavior in response to targeted down-regulation of the HER2/neu pathway, EHF is acutely up-regulated in human breast cancer cells following Adriamycin treatment, but down-regulated in tumor cells that survive neoadjuvant chemotherapy in breast cancer patients. Consistent with a model in which EHF down-regulation promotes tumor cell survival following therapy, low EHF expression in primary breast cancers is associated with a poor response to neoadjuvant chemotherapy and an increased risk of relapse in women with breast cancer. Collectively, our findings demonstrate that senescence is a conserved response to HER2/neu signaling inhibition in oncogene-addicted breast cancer cells and identify EHF as a potential regulator of HER2/neu inactivation-induced senescence and tumor cell survival following targeted therapy and chemotherapy.