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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: Review Complete

See all articles by Mingang Hao

Mingang Hao

University of Cincinnati - Department of Cancer Biology

SK Yeo

University of Cincinnati - Department of Cancer Biology

Alexis Harold

University of Cincinnati - Department of Cancer Biology

Yongguang Yang

University of Cincinnati - Department of Cancer Biology

Xiaoting Zhang

University of Cincinnati - Department of Cancer Biology

Jun-Lin Guan

University of Cincinnati - Department of Cancer Biology

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Abstract

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

Suggested Citation

Hao, Mingang and Yeo, Syn and Harold, Alexis and Yang, Yongguang and Zhang, Xiaoting and Guan, Jun-Lin, Autophagy Blockade Limits HER2+ Breast Cancer Tumorigenesis by Perturbing HER2 Trafficking to Be Released from Cells Via Small Extracellular Vesicles. Available at SSRN: https://ssrn.com/abstract=3661948 or http://dx.doi.org/10.2139/ssrn.3661948
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Mingang Hao

University of Cincinnati - Department of Cancer Biology

Cincinnati, OH 45267
United States

Syn Yeo

University of Cincinnati - Department of Cancer Biology ( email )

Cincinnati, OH 45267
United States

Alexis Harold

University of Cincinnati - Department of Cancer Biology ( email )

Cincinnati, OH 45267
United States

Yongguang Yang

University of Cincinnati - Department of Cancer Biology

Cincinnati, OH 45267
United States

Xiaoting Zhang

University of Cincinnati - Department of Cancer Biology

Cincinnati, OH 45267
United States

Jun-Lin Guan (Contact Author)

University of Cincinnati - Department of Cancer Biology ( email )

Cincinnati, OH 45267
United States

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