Autophagy-deficient breast cancer shows early escape from dormancy and recurrence following chemotherapy

Abstract

Abstract Breast cancer patients who respond to cancer therapies often end up with a distant recurrence of the disease. It is not clear why people with the same type of breast cancer respond to treatments differently, some escape from dormancy and relapse earlier than others. In addition, some tumor clones respond to immunotherapy while others do not. Here, we investigated the role of autophagy in expediting or delaying recurrence of neu overexpressing mammary carcinoma (MMC) following adriamycin (ADR) chemotherapy, and in affecting response to immunotherapy. We took two strategies, including a transient blockade of autophagy with chloroquine (CQ) which transiently blocks fusion of autophagosome and lysosome, and a stable knockdown of autophagy, which inhibits the formation of autophagosome in MMC. We found that while CQ prolonged tumor dormancy, a stable knockdown of autophagy resulted in early escape from dormancy and recurrence. Interestingly, MMC with a stable knockdown of autophagy contained an increased frequency of ADR-induced polyploidy cells which rendered MMC resistant to immunotherapy. On the other hand, a transient blockade of autophagy did not affect the sensitivity of MMC to immunotherapy. Our observations suggest that while chemotherapy-induced autophagy may facilitate tumor relapse, cell intrinsic autophagy delays tumor relapse by inhibiting the formation of polyploidy tumor cells. Our findings are consistent with other reports showing that autophagy-deficient cells contain polyploid nuclei because of increased levels of reactive oxygen species. Our results also suggest that responsiveness of breast cancer patients to neoadjuvant therapies might be determined by tumor intrinsic autophagy.