Autophagy Blockade Limits HER2+ Breast Cancer Tumorigenesis by Perturbing HER2 Trafficking and Promoting Release Via Small Extracellular Vesicles

Abstract

Autophagy modulation is an emerging strategy for cancer therapy. By deleting an essential autophagy gene or disrupting its autophagy function, we determined a mechanism of HER2+ breast cancer tumorigenesis by directly regulating the oncogenic driver. Disruption of FIP200-mediated autophagy reduced HER2 expression on the tumor cell surface and abolished mammary tumorigenesis in MMTV-Neu mice. Decreased HER2 surface expression was due to trafficking from the Golgi to the endocytic pathways instead of the plasma membrane. Autophagy inhibition led to HER2 accumulation in early and late endosomes associated with intraluminal vesicles and released from tumor cells in small extracellular vesicles (sEVs). Increased HER2 release from sEVs correlated with reduced tumor cell surface levels. Blocking sEVs secretion rescued HER2 levels in tumor cells. Our results demonstrate a role for autophagy to promote tumorigenesis in HER2+ breast cancer. This suggests that blocking autophagy could supplement current anti-HER2 agents for treating the disease.

Keywords: FIP200; HER2 intracellular trafficking; HER2-positive breast cancer; MMTV-Neu mice; autophagy; autophagy modulation for cancer therapy; endocytic pathways; mouse models of breast cancer; multi-vesicular bodies; small extracellular vesicles.