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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
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TGFBR3 supports anoikis through suppressing ATF4 signaling

Yu-Jhen Hsu1, Yih-Jia Yin1,2, Kai-Feng Tsai1

  • 1Institute of Molecular Medicine, National Tsing Hua University, Hsinchu 30013, Taiwan.

Journal of Cell Science
|August 1, 2022
PubMed

Insights

Transforming growth factor β receptor 3 (TGFBR3) loss in breast cancer impairs anoikis, a cell death process. Inhibiting TGFBR3 activates ATF4 signaling, suggesting therapeutic targets for specific breast cancer subtypes.

Area of Science:

  • Cell Biology
  • Cancer Research
  • Molecular Biology

Background:

  • Loss of cell adhesion and anoikis are hallmarks of epithelial morphogenesis and cancer.
  • Transforming growth factor β receptor 3 (TGFBR3) is often lost in breast cancer, but its role in anoikis is unclear.
  • Activating transcription factor 4 (ATF4) is implicated in cellular stress responses.

Purpose of the Study:

  • To investigate the role of TGFBR3 as an anoikis mediator in breast cancer.
  • To elucidate the relationship between TGFBR3, ATF4, and extracellular matrix (ECM) deprivation.
  • To identify potential therapeutic targets for breast cancer subtypes with altered TGFBR3 expression.

Main Methods:

  • Analysis of TGFBR3 expression in breast cancer tissues.
  • Investigating the effects of ECM deprivation on TGFBR3 expression and cell behavior.
  • Examining the impact of TGFBR3 inhibition on anoikis and ATF4 signaling.
  • Preclinical studies involving therapeutic inhibition of ATF4.

Main Results:

  • ECM loss promotes TGFBR3 expression, leading to cell aggregate differentiation and a low-adhesion phenotype.
  • TGFBR3 acts as an anoikis mediator by coordinating with ATF4.
  • Inhibition of TGFBR3 impairs epithelial anoikis through ATF4 activation.
  • Low TGFBR3 expression is associated with a breast cancer subtype exhibiting adhesion defects.

Conclusions:

  • TGFBR3 plays a crucial role in mediating anoikis, particularly under conditions of ECM loss.
  • The TGFBR3-ATF4 axis represents a potential therapeutic strategy for breast cancer patients with low TGFBR3.
  • Targeting ATF4 may be beneficial for a specific subgroup of breast cancer patients.
Keywords:
Activating transcription factor 4AnoikisBreast cancerIntegrated stress responseTransforming growth factor β

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