title: 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.affiliation: Goodman Cancer Research Centre, 1160 Pine Avenue West, McGill University, Montréal, Québec H3A 1A3 (XL, VG) and Departments of Biochemistry, Medicine and Oncology, 3655 Promenade Sir William Osler, McGill University, Montréal, Québec H3G 1Y6 (VG), Canada .
authors.forename: Xingxing
authors.initials: X
authors.lastname: Liu
authors.affiliation: Goodman Cancer Research Centre, 1160 Pine Avenue West, McGill University, Montréal, Québec H3A 1A3 (XL, VG) and Departments of Biochemistry, Medicine and Oncology, 3655 Promenade Sir William Osler, McGill University, Montréal, Québec H3G 1Y6 (VG), Canada .
authors.forename: Vincent
authors.initials: V
authors.lastname: Giguère
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D017353:Gene Deletion; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000473:pathology*; D051379:Mice; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000172:deficiency* / Q000235:genetics*; D017154:Stromal Cells / Q000473:pathology; D051155:Wnt1 Protein / Q000378:metabolism*
chemical_list: C583557:IGF1 protein, human; D018168:Receptors, Retinoic Acid; C495247:WNT1 protein, human; D051155:Wnt1 Protein; C082925:retinoic acid receptor beta; D007334:Insulin-Like Growth Factor I; D051057:Proto-Oncogene Proteins c-akt
keywords: Breast cancer; IGF-1; nuclear receptor; oncogene; retinoid