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

ABSTRACT: Retinoic acid receptor ? (RAR?) has been proposed to act as a tumor suppressor in breast cancer. In contrast, recent data have shown that RAR? promotes ERBB2-induced mammary gland tumorigenesis through remodeling of the stromal compartment and activation of cancer-associated fibroblasts. However, it is currently unknown whether RAR? 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 RAR? 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 RAR?, 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 RAR?-dependent retinoid signaling could provide a therapeutic avenue to treat poor outcome breast cancers.

SUBMITTER: Liu X 

PROVIDER: S-EPMC4242291 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature