Year: 2022
Type: article
Abstract: Cancer cells can disseminate during very early and sometimes asymptomatic stages of tumor progression. Though biological barriers to tumorigenesis have been identified and characterized, the mechanisms that limit early dissemination remain largely unknown. We report here that the orphan nuclear receptor nuclear receptor subfamily 2, group F, member 1 (NR2F1)/COUP-TF1 serves as a barrier to early dissemination. NR2F1 expression was decreased in patient ductal carcinoma in situ (DCIS) samples. High-resolution intravital imaging of HER2+ early-stage cancer cells revealed that loss of function of NR2F1 increased in vivo dissemination and was accompanied by decreased E-cadherin expression, activation of wingless-type MMTV integration site family, member 1 (WNT)-dependent β-catenin signaling, disorganized laminin 5 deposition, and increased expression of epithelial-mesenchymal transition (EMT) genes such as twist basic helix-loop-helix transcription factor 1 (TWIST1), zinc finger E-box binding homeobox 1 (ZEB1), and paired related homeobox 1 (PRRX1). Furthermore, downregulation of NR2F1 promoted a hybrid luminal/basal phenotype. NR2F1 expression was positively regulated by p38α signaling and repressed by HER2 and WNT4 pathways. Finally, early cancer cells with NR2F1LOW/PRRX1HIGH staining were observed in DCIS samples. Together, these findings reveal the existence of an inhibitory mechanism of dissemination regulated by NR2F1 in early-stage breast cancer cells. SIGNIFICANCE: During early stages of breast cancer progression, HER2-mediated suppression of NR2F1 promotes dissemination by inducing EMT and a hybrid luminal/basal-like program.
Source: Cancer Research
Language: English
Topic: Cancer Cells and Metastasis
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Role of Cancer Stem Cells in Malignant Progression of Ductal Carcinoma in Situ., Mechanisms of quiescence and pluripotency in disseminated tumor cells, Identifying the Molecular and Cellular Basis of Invasive Phenotype in Human DCIS, Multiphoton Laser Scanning Microscope, Defining the role of type III collagen and the collagen-binding receptor DDR1 in metastatic dormancy, Protrusion plasticity during in vivo tumor cell migration, A novel N-Ras pathway driving DCIS to basal-like breast cancer, Frontiers Clinical and Translational Science Institute at the University of Kansas, The Kansas Institute for Precision Medicine, The University of Kansas Cancer Center, The Tisch Cancer Institute - Cancer Center Support Grant
OpenAlex ID: W4224443288