GSBS Dissertations and Theses

ORCID ID

0000-0003-4803-5926

Publication Date

2019-06-27

Document Type

Doctoral Dissertation

Academic Program

Cancer Biology

Department

Molecular, Cell and Cancer Biology

First Thesis Advisor

Leslie M. Shaw, PhD

Keywords

Beclin 1, HRS, Endocytosis, Tumor Proliferation, Breast Cancer, Metabolism

Abstract

BECN1 is a haploinsufficient tumor suppressor gene that is monoallelically deleted or epigenetically silenced in many human cancers. In breast cancer, 40% of tumors exhibit monoallelic deletion of Beclin 1. Additionally, low Beclin 1 mRNA expression is observed in aggressive breast cancer subtypes and reduced expression is an independent predictor of overall patient survival. The role of Beclin 1 in cancer has almost exclusively been attributed to its function in autophagy. However, our lab demonstrated an alternative role for Beclin 1 in the regulation of growth factor receptor signaling that could contribute to cancer. The goal of my thesis project was to investigate the molecular basis by which Beclin 1 regulates breast tumor growth and progression in vivo.

Using in vivo models, I discovered that Beclin 1 promotes endosomal recruitment of hepatocyte growth factor tyrosine kinase substrate (HRS), which is necessary for sorting receptors to intraluminal vesicles for signal silencing and degradation. Beclin 1-dependent recruitment of HRS results in the autophagy-independent regulation of endocytic trafficking and degradation of the epidermal growth factor (EGFR) and transferrin (TFR1) receptors. When Beclin 1 expression is low, endosomal HRS recruitment is reduced and receptor function is sustained to drive tumor proliferation. An autophagy-independent role for Beclin 1 in regulating tumor metabolism was also observed. Collectively, my results demonstrate a novel role for Beclin 1 in impeding tumor growth by coordinating the regulation of growth promoting receptors. These data provide an explanation for how low levels of Beclin 1 facilitate tumor proliferation and contribute to poor cancer outcomes, independently of autophagy.

DOI

10.13028/8zqt-8797

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Licensed under a Creative Commons license

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This work is licensed under a Creative Commons Attribution 4.0 License.

Available for download on Tuesday, June 01, 2021

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