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The Role of ARID1A in the Nonestrogenic Modulation of IGF-1 Signaling

Sham Jdeed1, Edina Erdős2, Bálint L Bálint2

  • 1Department of Clinical Oncology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.

Molecular Cancer Research : MCR
|March 23, 2022
PubMed

Insights

Repurposed drugs bexarotene and carvedilol suppress breast cancer growth by altering ARID1A protein levels and regulating insulin-like growth factor signaling pathways. This offers a new therapeutic strategy for breast cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • ARID1A is a tumor suppressor protein involved in cancer gene expression.
  • Retinoid X receptor ligands affect breast cell proliferation and differentiation.
  • Targeting ARID1A pharmacologically remains a challenge.

Purpose of the Study:

  • To investigate the effect of bexarotene (Bex) and carvedilol (Carv) on ARID1A levels and breast cancer cell proliferation.
  • To elucidate the mechanism by which Bex + Carv impacts gene expression, particularly related to insulin-like growth factor (IGF) signaling.
  • To explore the therapeutic potential of modulating ARID1A activity in breast cancer.

Main Methods:

  • Cell proliferation assays using MCF10DCIS.com and MCF-7 breast cancer cell lines.
  • Western blotting to assess ARID1A protein levels.
  • Chromatin immunoprecipitation sequencing (ChIP-seq) to analyze genomic distribution of ARID1A and H3K27ac.
  • Gene knockdown experiments for ARID1A.
  • In vitro assays using IGF-1 receptor neutralizing antibody.

Main Results:

  • Low-dose Bex combined with Carv suppressed proliferation and reduced ARID1A levels in breast cancer cells.
  • Bex + Carv altered the genomic distribution of ARID1A and H3K27ac at IGF signaling-related sites, suppressing IGF-1 receptor (IGF-1R) and IRS1.
  • ARID1A knockdown increased IGF-1R levels and abrogated the suppressive effects of Bex + Carv, while stimulating proliferation.
  • Elevated IGF-1R or IRS1 expression correlated with poor survival in ER-negative breast cancer patients.

Conclusions:

  • ARID1A redistribution directly impacts the expression and growth regulation of IGF-1-related genes.
  • Repurposed drugs Bex and Carv can induce ARID1A redistribution under nonestrogenic conditions.
  • Pharmacologic modulation of ARID1A offers a potential strategy to downregulate protumorigenic IGF-1 activity in breast cancer.

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