IGH3 in the breast cancer tumor microenvironment increases TGF- signaling to promote cancer progression

Loading...
Thumbnail Image

Date

2021

Journal Title

Journal ISSN

Volume Title

Repository Usage Stats

60
views
23
downloads

Abstract

The secreted extracellular protein, transforming growth factor  induced (TGFBI or IGH3), has context dependent tumor suppressor and tumor promoting roles, similar to TGF-, in part by promoting chemotherapy sensitivity, but then increased IGH3 levels promote cancer progression, with elevated levels correlating to poorer clinical outcomes. IGH3 is regulated by the transforming growth factor-β (TGF-β) signaling pathway, which is an important regulator of breast cancer progression. However, how the breast cancer microenvironment regulates TGF-β signaling during breast cancer progression remains poorly understood. In previous studies, we identified IGH3 as a secreted protein able to promote TGF- signaling. Here, we demonstrate that IGH3 promotes breast tumor growth by promoting activation of the TGF-1 ligand from its latent form in the breast cancer tumor microenvironment. CRISPR/Cas9 silencing of IGH3 decreased tumor growth and decreased activation of latent TGF-1 in a breast cancer models. Mechanistically, IGH3 activates latent TGF-1 through its cysteine rich domain, specifically cysteine 65, and partially through its FAS1-4 domain. Increased IGH3 expression in breast cancer patients correlates with poorer clinical outcomes. These results indicate that TGF-β-mediated induction of IGH3 expression is one mechanism for sustaining elevated TGF-β signaling in the breast cancer tumor microenvironment, with IGH3 setting up positive feed forward loop by promoting activation of latent TGF-1, driving breast cancer growth. Thus, mechanisms to target IGH3 have potential utility in advanced cancers, while assessing IGH3 levels could be a biomarker for chemotherapy resistance and tumor progression.

Department

Description

Provenance

Citation

Citation

Corona, Armando (2021). IGH3 in the breast cancer tumor microenvironment increases TGF- signaling to promote cancer progression. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/23737.

Collections


Dukes student scholarship is made available to the public using a Creative Commons Attribution / Non-commercial / No derivative (CC-BY-NC-ND) license.