Autophagy Blockade Limits HER2+ Breast Cancer Tumorigenesis by Perturbing HER2 Trafficking to Be Released from Cells Via Small Extracellular Vesicles
54 Pages Posted: 26 Aug 2020 Publication Status: PublishedMore...
Autophagy modulation is an emerging strategy for cancer therapy, including its use in combination with other molecular targeting agents. However, due to its broad impact on multiple cellular functions, autophagy has been shown to play both tumor suppressive and tumor promoting functions in different contexts and models. In this study, we employed unique mouse models that delete an essential autophagy gene Fip200 (i.e. cKO mice) or specifically disrupt Fip200’s autophagy function (i.e. cKI mice) in HER2-positive breast cancer to reveal a novel mechanism for autophagy to promote mammary tumorigenesis by directly regulating the oncogenic driver HER2. Disruption of FIP200-mediated autophagy reduced HER2 expression on the tumor cell surface and essentially abolished mammary tumorigenesis in MMTV-Neu mice. The decreased surface expression of HER2 was not caused by changes at transcriptional levels, protein degradation or elevated endocytosis, but rather due to altered intracellular trafficking from the Golgi to the endocytic pathways instead of the plasma membrane. Autophagy inhibition led to HER2 accumulation in both early and late endosomes/multiple vesicular bodies associated with the intraluminal vesicles and eventually released from tumor cells in small extracellular vesicles (sEVs). The increased HER2 release from sEVs correlated with its reduced levels on tumor cell surface, and blocking sEVs secretion rescued HER2 levels in tumor cells. Together, our results demonstrate a new mechanism for autophagy to promote mammary tumorigenesis in HER2-positive breast cancer, which suggests that blocking autophagy could supplement current anti-HER2 agents for treating the disease.
Keywords: HER2-positive breast cancer, autophagy, FIP200, small extracellular vesicles
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