title: Stromal retinoic acid receptor beta promotes mammary gland tumorigenesis.
abstract: Retinoic acid is a potent differentiation and antiproliferative agent of breast cancer cells, and one of its receptors, retinoic acid receptor β (RARβ), has been proposed to act as a tumor suppressor. In contrast, we report herein that inactivation of Rarb in the mouse results in a protective effect against ErbB2-induced mammary gland tumorigenesis. Strikingly, tissue recombination experiments indicate that the presence of Rarb in the stromal compartment is essential for the growth of mammary carcinoma. Ablation of Rarb leads to a remodeling of the stroma during tumor progression that includes a decrease in angiogenesis, in the recruitment of inflammatory cells, and in the number myofibroblasts. In agreement with this finding, we observed that a markedly reduced expression of chemokine (C-X-C motif) ligand 12 (Cxcl12) in the stroma of Rarb-null mice is accompanied by a decrease in the CXCL12/chemokine C-X-C receptor 4 (CXCR4)/ErbB2 signaling axis in the tumors. Relevance to the human disease is underlined by the finding that gene-expression profiling of the Rarb-deficient mammary stromal compartment identified an ortholog RARβ signature in human microdissected breast tissues that differentiates tumor from normal stroma. Our study thus implicates RARβ in promoting tumorigenesis and suggests that retinoid-based approaches for the prevention and treatment of breast cancer should be redesigned.
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada H3A 1A3.
authors.forename: Xingxing
authors.initials: X
authors.lastname: Liu
authors.forename: Mélanie
authors.initials: M
authors.lastname: Nugoli
authors.forename: Julie
authors.initials: J
authors.lastname: Laferrière
authors.forename: Sadiq M
authors.initials: SM
authors.lastname: Saleh
authors.forename: Ian G
authors.initials: IG
authors.lastname: Rodrigue-Gervais
authors.forename: Maya
authors.initials: M
authors.lastname: Saleh
authors.forename: Morag
authors.initials: M
authors.lastname: Park
authors.forename: Michael T
authors.initials: MT
authors.lastname: Hallett
authors.forename: William J
authors.initials: WJ
authors.lastname: Muller
authors.forename: Vincent
authors.initials: V
authors.lastname: Giguère
mesh_terms: D000818:Animals; D054377:Chemokine CXCL12 / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D008321:Mammary Glands, Animal / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009857:Oncogenes; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D012176:Retinoids / Q000737:chemistry; D015398:Signal Transduction; D017154:Stromal Cells / Q000166:cytology*
chemical_list: D054377:Chemokine CXCL12; D018719:Erb-b2 Receptor Tyrosine Kinases; D019718:Receptors, CXCR4; D018168:Receptors, Retinoic Acid; D012176:Retinoids; C514936:CXCR4 protein, mouse; C515256:Cxcl12 protein, mouse; C082925:retinoic acid receptor beta; C524056:Erbb2 protein, mouse