Extracellular superoxide dismutase inhibits hepatocyte growth factor-mediated breast cancer-fibroblast interactions

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Extracellular superoxide dismutase (EcSOD) exhibits tumor-suppressive effects in breast cancer.
• The HGF/c-Met signaling pathway is implicated in cancer progression and stromal interactions.
• Fibroblast activation and the tumor microenvironment play critical roles in breast cancer development.

Purpose of the Study:

• To investigate the inhibitory mechanisms of EcSOD on breast cancer cells, specifically focusing on RTK signaling.
• To elucidate the role of EcSOD in regulating cancer-fibroblast interactions mediated by HGF/c-Met.
• To determine the contribution of oxidative stress and fibroblast-derived factors to tumor growth and invasion.

Main Methods:

• RTK signaling array and extracellular protein array to identify molecular interactions.
• Co-culture experiments using MDA-MB231 breast cancer cells and normal fibroblasts (RMF) or HGF-overexpressing fibroblasts (RMF-HGF).
• In vitro assays (Matrigel growth, collagen contraction) and in vivo orthotopic tumor growth models.
• Assessment of reactive oxygen species (ROS) generation and targeting of NADPH oxidase 4 (Nox4).

Main Results:

• EcSOD inhibited c-Met phosphorylation and its downstream kinase c-Abl in MDA-MB231 cells.
• EcSOD overexpression upregulated thrombospondin 1 (TSP-1), a scavenger of HGF.
• EcSOD and a SOD mimetic (MnTE-2-PyP) inhibited HGF-stimulated growth and invasion of breast cancer cells.
• Fibroblasts overexpressing HGF (RMF-HGF) promoted tumor growth, but this effect was attenuated by co-culture with EcSOD-overexpressing cells.
• RMF-HGF cells exhibited increased NADPH oxidase 4 (Nox4) expression, contributing to an oxidative tumor microenvironment.
• Scavenging ROS with EcSOD significantly inhibited RMF-HGF-stimulated orthotopic tumor growth.

Conclusions:

• Loss of EcSOD in breast cancer promotes HGF/c-Met-mediated cancer-fibroblast interactions.
• EcSOD exerts tumor suppressive effects by modulating RTK signaling and the tumor microenvironment.
• Targeting oxidative stress and pro-oxidant fibroblast activity represents a potential therapeutic strategy for breast cancer.