Differential Regulation of Fibronectin Expression and Fibrillogenesis by Autocrine TGF- β1 Signaling in Malignant and Benign Mammary Epithelial Cells

Int J Biochem Cell Biol. 2023 Oct 20:106478. doi: 10.1016/j.biocel.2023.106478. Online ahead of print.ABSTRACTRemodeling of the extracellular matrix (ECM) is a key hallmark of cancer progression. A critical component of ECM remodeling is the assembly of the ECM protein fibronectin (FN) into insoluble fibrils, which provide a scaffold for invading vascular endothelial cells and escaping cancer cells, as well as a framework for collagen deposition and oncogenic cytokine tethering. FN fibril assembly is induced by Transforming Growth Factor-β1 (TGF-β1), which was originally identified for its role in malignant transformation. Addition of exogenous TGF-β1 drives FN fibril assembly while also upregulating endogenous TGF-β1 expression and autocrine signaling. In the current study, we sought to determine if autocrine TGF-β1 signaling plays a role in FN fibril formation in either MCF10A mammary epithelial cells, which behave similarly to healthy epithelia, or malignant MDA- MB-231 breast cancer cells. Our results show two interesting findings: first, malignant MDA-MB- 231 cells assemble less FN into fibrils, despite expressing and secreting more soluble FN; second, autocrine TGF-β1 signaling is required for FN fibril formation in MCF10A epithelial cells, even in the presence of exogenous, active TGF-β1. This suggests that autocrine TGF-β1 is signaling through distinct pathways from active exogenous TGF-β1. We hypothesized that this signaling was mediated by interactions betw...

Source: The International Journal of Biochemistry and Cell Biology - October 22, 2023 Category: Biochemistry Authors: Michael M Sofroniou Christopher A Lemmon Source Type: research