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 lay dormant for extended periods before they reawaken and develop into lethal metastases. We seek to delineate whether autophagy impacts the survival of dormant tumor cells, or alternatively, influences their ability to exit from dormancy and produce overt metastatic disease. We have utilized a three-dimensional culture models as well as generated an in vivo mouse transgenic model to assay cellular quiescence and tumor dormancy in breast cancer. To date, our studies have uncovered two opposing, context-dependent functions for autophagy that impact late recurrent metastatic progression. On the one hand, in breast tumors driven by the PI3K pathway, autophagy restricts proliferation and maintains a quiescent state. On the other, in tumors with hyper-activation of the Ras/MAPK pathway, autophagy promotes invasive behavior and alters epithelial differentiation and secretion. For our ongoing in vivo studies, we will place high priority on elaborating whether and how these two paradoxical functions for the autophagy pathway impact late disease progression in breast cancer. In fact, our in vivo studies over the past year indicate that autophagy inhibition promotes, rather than impedes the metastasis of polyoma middle T (PyMT) mammary cancers in vivo, which have unexpected implications for autophagy in late recurrent disease by modulating the activation of dormant tumor cells to produce overt metastatic disease. We will further corroborate this hypothesis in the upcoming years using the primary in vivo models developed through this project.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2013
- Accession Number
- ADA599498
Entities
People
- Jayanta Debnath
Organizations
- University of California, San Francisco