Characterization of the CD49f + /CD44 + /CD24 − single-cell derived stem cell population in basal-like DCIS cells

// Nadire Duru 1 , Ramkishore Gernapudi 1 , Pang-Kuo Lo 1 , Yuan Yao 1 , Benjamin Wolfson 1 , Yongshu Zhang 1 , Qun Zhou 1 1 Department of Biochemistry and Molecular Biology, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA Correspondence to: Qun Zhou, email: qzhou@som.umaryland.edu Keywords: tumor heterogeneity, single cell cloning, cancer stem cells, DCIS, non-coding RNAs Received: March 29, 2016      Accepted: June 09, 2016      Published: June 21, 2016 ABSTRACT The molecular mechanisms responsible for the Ductal Carcinoma in Situ (DCIS)-Invasive Ductal Carcinoma (IDC) transition have yet to be elucidated. Due to the lack of molecularly targeted therapies, basal-like DCIS has a high risk of recurrence and progression to invasive and metastatic cancers. In this study, by applying a novel single-cell clonogenic approach with the CD49f + /CD44 + /CD24 − surface markers, we characterized the aggressive clones that have enhanced self-renewal, migratory and invasive capacities derived from a human DCIS model cell line MCF10DCIS. The aggressive clones had elevated ALDH1 activity, lower global DNA methylation and increased expression of stem cell related genes, especially concurrent activation of SOX2/OCT4. In addition, we showed that the aggressive clones have increased expression of lincRNA-RoR and miR-10b compared to non-aggressive clones, which enhance their self-renewal and invasive abilities. Finally, we confirmed our in vitro results in vivo, demonstrating that aggressive clones were capable of forming tumors in nude mice, whereas non-aggressive clones were not. Our data suggest that lincRNA-RoR and miR10b could be used to distinguish aggressive clones from non-aggressive clones within the heterogeneous CD49f + /CD44 + /CD24 − DCIS population. Our findings also provide the foundation to develop new chemoprevention agents for DCIS-IDC transition.