Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

C. Rodriguez-Tirado and N. Kale contributed equally to this article.

Current address for N. Kale: UCSF Helen Diller Comprehensive Family Cancer Center, University of California, San Fransisco, California; current address for M.J. Carlini, Columbia University, New York, New York; ccurrent address for N. Shrivastava, Department of Pathology, Albert Einstein College of Medicine, Bronx, New York; current address for B. Khalil, Western Atlantic University School of Medicine, Plantation, Florida; and current address for J. Ji, Rutgers University, New Brunswick, New Jersey.

Carolina Rodriguez-Tirado, Nupura Kale, Maria J. Carlini, Nitisha Shrivastava, Alcina A. Rodrigues, Bassem D. Khalil, Jose Javier Bravo-Cordero, Yan Hong, Melissa Alexander, Jiayi Ji, Fariba Behbod, Maria Soledad Sosa; NR2F1 Is a Barrier to Dissemination of Early-Stage Breast Cancer Cells. Cancer Res 15 June 2022; 82 (12): 2313–2326. https://doi.org/10.1158/0008-5472.CAN-21-4145

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.

During early stages of breast cancer progression, HER2-mediated suppression of NR2F1 promotes dissemination by inducing EMT and a hybrid luminal/basal-like program.

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