Translational control of breast cancer plasticity

Area of Science:

• Molecular Biology
• Cancer Research
• Cell Biology

Background:

• Cancer cell plasticity, the ability to acquire stem-cell-like properties, drives disease progression and poses a significant therapeutic challenge.
• Understanding the molecular mechanisms underlying cancer plasticity is crucial for developing effective treatments.

Purpose of the Study:

• To investigate the mechanisms by which breast cancer cells acquire plasticity and stem-cell-like phenotypes.
• To identify potential therapeutic targets for overcoming drug resistance and metastasis in breast cancer.

Main Methods:

• Analysis of NANOG, SNAIL, and NODAL transcript isoforms with distinct 5' Untranslated Regions (5'UTRs) in breast cancer cells.
• Investigating the translational regulation of these isoforms under hypoxic conditions and in response to mTOR inhibitors and chemotherapeutics.
• Evaluating the efficacy of drugs targeting the Integrated Stress Response, such as ISRIB, in modulating cancer cell plasticity.

Main Results:

• Breast cancer cells express multiple NANOG, SNAIL, and NODAL isoforms with varying 5'UTRs.
• Hypoxia, mTOR inhibitors, and chemotherapeutics stimulate the translation of specific isoforms, leading to stem-cell-like phenotypes.
• The Integrated Stress Response, mediated by eIF2α phosphorylation, drives this translational reprogramming and subsequent plasticity.
• Inhibiting the Integrated Stress Response with drugs like ISRIB can overcome the induction of plasticity.

Conclusions:

• A novel mechanism involving the translational control of specific NANOG, SNAIL, and NODAL isoforms drives breast cancer cell plasticity.
• The Integrated Stress Response plays a key role in mediating this plasticity, contributing to therapeutic challenges.
• Targeting translational reprogramming via the Integrated Stress Response offers a promising strategy to combat drug resistance and metastasis in breast cancer.