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.

自噬调节是一种新兴的癌症治疗策略。通过删除一个重要的自噬基因或破坏其自噬功能，我们通过直接调节致癌驱动因子确定了 HER2+ 乳腺癌肿瘤发生的机制。FIP200 介导的自噬的破坏降低了肿瘤细胞表面的 HER2 表达，并消除了 MMTV-Neu 小鼠的乳腺肿瘤发生。HER2 表面表达减少是由于从高尔基体转运到内吞途径而不是质膜。自噬抑制导致 HER2 在与腔内囊泡相关的早期和晚期内体中积累，并从小细胞外囊泡 (sEVs) 中的肿瘤细胞中释放出来。sEV 中 HER2 释放的增加与肿瘤细胞表面水平的降低有关。阻断 sEVs 的分泌可以挽救肿瘤细胞中的 HER2 水平。我们的结果证明了自噬在 HER2+ 乳腺癌中促进肿瘤发生的作用。这表明阻断自噬可以补充目前用于治疗该疾病的抗 HER2 药物。