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Stromal retinoic acid receptor beta promotes mammary gland tumorigenesis

Xingxing Liu1, Mélanie Nugoli, Julie Laferrière

  • 1Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada H3A 1A3.

Proceedings of the National Academy of Sciences of the United States of America
|December 29, 2010
PubMed

Insights

Retinoic acid receptor beta (RARβ) inactivation protects against breast cancer in mice by altering the tumor stroma. This finding challenges the traditional view of RARβ as a tumor suppressor and suggests new therapeutic strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Retinoic acid is known for its anti-cancer properties, with retinoic acid receptor beta (RARβ) previously suggested to be a tumor suppressor in breast cancer.
  • The role of RARβ in mammary gland tumorigenesis, particularly in the context of ErbB2-driven cancers, remains incompletely understood.

Purpose of the Study:

  • To investigate the role of retinoic acid receptor beta (RARβ) in ErbB2-induced mammary gland tumorigenesis.
  • To elucidate the mechanisms by which RARβ influences tumor growth and the tumor microenvironment.

Main Methods:

  • Inactivation of the Rarb gene in a mouse model of ErbB2-induced mammary gland cancer.
  • Tissue recombination experiments to assess the role of RARβ in different cellular compartments.
  • Analysis of stromal remodeling, including angiogenesis, inflammatory cell recruitment, and myofibroblast presence.
  • Gene expression profiling of mammary stromal compartments and analysis of the CXCL12/CXCR4/ErbB2 signaling axis.

Main Results:

  • Inactivation of Rarb conferred a protective effect against ErbB2-induced mammary gland tumorigenesis.
  • RARβ in the stromal compartment was found to be essential for mammary carcinoma growth.
  • Rarb ablation led to decreased angiogenesis, reduced inflammatory cell infiltration, and fewer myofibroblasts in the tumor stroma.
  • Reduced stromal Cxcl12 expression and a diminished CXCL12/CXCR4/ErbB2 signaling axis were observed in Rarb-null mice.
  • A conserved RARβ signature in human breast tissues differentiated tumor from normal stroma.

Conclusions:

  • Retinoic acid receptor beta (RARβ) actively promotes mammary tumorigenesis, contradicting its proposed tumor suppressor role.
  • RARβ influences tumor growth by modulating the tumor stroma, affecting angiogenesis, inflammation, and myofibroblast populations.
  • These findings necessitate a re-evaluation and redesign of retinoid-based therapeutic and preventive strategies for breast cancer.

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