Inactivation of RARβ inhibits Wnt1-induced mammary tumorigenesis by suppressing epithelial-mesenchymal transitions.

Abstract

Retinoic acid receptor β (RARβ) has been proposed to act as a tumor suppressor in breast cancer. In contrast, recent data have shown that RARβ promotes ERBB2-induced mammary gland tumorigenesis through remodeling of the stromal compartment and activation of cancer-associated fibroblasts. However, it is currently unknown whether RARβ oncogenic activity is specific to ERBB2-induced tumors, or whether it influences the initiation and progression of other breast cancer subtypes. Accordingly, we set out to investigate the involvement of RARβ in basal-like breast cancer using mouse mammary tumor virus (MMTV)-wingless-related integration site 1 (Wnt1)-induced mammary gland tumorigenesis as a model system. We found that compared with wild type mice, inactivation of Rarb resulted in a lengthy delay in Wnt1-induced mammary gland tumorigenesis and in a significantly slower tumor growth rate. Ablation of Rarb altered the composition of the stroma, repressed the activation of cancer-associated fibroblasts, and reduced the recruitment of inflammatory cells and angiogenesis. Reduced expression of IGF-1 and activity of its downstream signaling pathway contribute to attenuate EMT in the Rarb-null tumors. Our results show that, in the absence of retinoid signaling via RARβ, reduced IGF-1 signaling results in suppression of epithelial-mesenchymal transition and delays tumorigenesis induced by the Wnt1 oncogene. Accordingly, our work reinforces the concept that antagonizing RARβ-dependent retinoid signaling could provide a therapeutic avenue to treat poor outcome breast cancers.

• Authors: Xingxing Liu, Vincent Giguère
• Journal: Nuclear receptor signaling (Nucl Recept Signal) Vol. 12 Pg. e004 ( 2014) ISSN: 1550-7629 [Electronic] United States
• PMID: 25422594 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• IGF1 protein, human
• Receptors, Retinoic Acid
• WNT1 protein, human
• Wnt1 Protein
• retinoic acid receptor beta
• Insulin-Like Growth Factor I
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Carcinogenesis (genetics)
• Cell Line, Tumor
• Down-Regulation (genetics)
• Epithelial-Mesenchymal Transition (genetics)
• Gene Deletion
• Humans
• Insulin-Like Growth Factor I (metabolism)
• Mammary Neoplasms, Experimental (genetics, pathology)
• Mice
• Proto-Oncogene Proteins c-akt (metabolism)
• Receptors, Retinoic Acid (deficiency, genetics)
• Stromal Cells (pathology)
• Wnt1 Protein (metabolism)