Eliminating Late Recurrence to Eradicate Breast Cancer
Abstract
Breast cancer patients exhibit high rates of late recurrent metastatic disease, which arise from tumor cells that lie dormant for extended periods before reawakening and developing into lethal metastases. We seek to delineate whether autophagy, a tightly controlled lysosomal digestion process, impacts the survival of dormant tumor cells, or alternatively, influences their ability to exit from dormancy and produce overt metastatic disease. Over the past year, we have obtained evidence using two immune competent mammary cancer models that autophagy inhibition promotes, rather than impedes, the development of overt metastasis in vivo. These findings suggest that autophagy restricts late recurrent disease by preventing the ability of dormant, disseminated tumor cells to exit from quiescent states and produce overt metastatic disease. Our initial mechanistic studies suggest multiple mechanisms by which autophagy restricts metastasis, including: 1) the cell autonomous control of focal adhesion signaling or proliferative outgrowth, or 2) the altered secretion of factors modulating efficient metastatic outgrowth and colonization. In parallel, we have created a polyoma middle T (PyMT)-based transgenic model exhibiting delayed kinetics with respect to the development of breast cancer macro-metastasis and one in which we can genetically ablate autophagy with both tumor cell and temporal/stage specificity. We are currently using this slow progression model to determine how to best modulate autophagy to prevent both metastatic colonization and late recurrence in vivo.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2014
- Accession Number
- ADA613396
Entities
People
- Jayanta Debnath
Organizations
- University of California, San Francisco