Eliminating Late Recurrence to Eradicate Breast Cancer
Annual rept. 1 Sep 2014-31 Aug 2015
CALIFORNIA UNIV REGENTS SAN FRANCISCO
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Late recurrent disease, which arise s from tumor cells that lie dormant for extended periods before reawakening into lethal metastases , is a principal cause of mortality in breast cancer patients. We are dissecting how autophagy, a tightly controlled lysosomal digestion process, impacts breast cancer dormancy and metastatic colonization. Previously, we discovered that autophagy in breast cancer cells prevents metastatic colonization in vivo. Over the last year, we genetically ablated autophagy in a transgenic mammary cancer model that exhibits delayed kinetics with respect to the development of metastasis. Our results in this slow progression model also indicate that tumor cell autophagy impedes metastatic colonization. In addition, we identified the selective autophagy receptor, NBR1, as a key mediator of metastatic colonization in vivo as well as focal adhesion turnover in breast cancer cells in vitro. These results support our model that tumor cell autophagy restricts late recurrent disease by preventing the ability of dormant, disseminated tumor cells to exit from quiescent states by impeding focal adhesion remodeling and function. Lastly, we have found that systemic inhibition of autophagy , using the anti - malarial chloroquine , leads to reduced pulmonary metastasis. This contrasts with our results obtained with genetic autophagy inhibition specific to tumor cells and motivates the hypothesis that autophagy inhibition in host stromal constituents, rather than tumor cells, may direct the potentially beneficial effects of anti - malarial treatment in preventing breast cancer metastasis.
- Anatomy and Physiology
- Medicine and Medical Research