TGFBR3 supports anoikis through suppressing ATF4 signaling.
Yu-Jhen HsuYih-Jia YinKai-Feng TsaiCian-Chun JianZi-Wen LiangChien-Yu HsuChun-Chao WangPublished in: Journal of cell science (2022)
Epithelial morphogenesis and oncogenic transformation can cause loss of cell adhesion, and detached cells are eliminated by anoikis. Here, we reveal that transforming growth factor β receptor 3 (TGFBR3) acts as an anoikis mediator through the coordination of activating transcription factor 4 (ATF4). In breast cancer tissues, TGFBR3 is progressively lost, but elevated TGFBR3 is associated with a histologic subtype characterized by cellular adhesion defects. Dissecting the impact of extracellular matrix (ECM) deprivation, we demonstrate that ECM loss promotes TGFBR3 expression, which in turn causes differentiation of cell aggregates, conferring a low-adhesion phenotype, and drives the intrinsic apoptotic pathway. We demonstrate that inhibition of TGFBR3 impairs epithelial anoikis by activating ATF4 signaling. These preclinical findings provide a rationale for therapeutic inhibition of ATF4 in the subgroup of breast cancer patients with low TGFBR3 expression.
Keyphrases
- transcription factor
- extracellular matrix
- transforming growth factor
- cell adhesion
- endoplasmic reticulum stress
- poor prognosis
- induced apoptosis
- signaling pathway
- epithelial mesenchymal transition
- single cell
- gene expression
- cell therapy
- binding protein
- randomized controlled trial
- genome wide
- biofilm formation
- oxidative stress
- cystic fibrosis
- sensitive detection
- escherichia coli
- candida albicans
- breast cancer risk
- placebo controlled