Triple negative breast cancers comprise a highly tumorigenic cell subpopulation detectable by its high responsiveness to a Sox2 regulatory region 2 (SRR2) reporter

// Karen Jung 1,* , Nidhi Gupta 2,* , Peng Wang 2 , Jamie T. Lewis 3 , Keshav Gopal 2 , Fang Wu 2 , Xiaoxia Ye 2 , Abdulraheem Alshareef 2 , Bassam S. Abdulkarim 4 , Donna N. Douglas 3 , Norman M. Kneteman 3 and Raymond Lai 1,2,5 1 Department of Oncology, University of Alberta, Edmonton, Alberta, Canada 2 Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada 3 Department of Surgery, University of Alberta, Edmonton, Alberta, Canada 4 Department of Oncology, McGill University, Montreal, Quebec, Canada 5 DynaLIFE Dx Medical Laboratories, Edmonton, Alberta, Canada * These authors are Co-first authors Correspondence to: Raymond Lai, email: // Keywords : breast cancer, tumour cell heterogeneity, Sox2, SRR2 Received : January 21, 2015 Accepted : February 17, 2015 Published : April 30, 2015 Abstract We have recently described a novel phenotypic dichotomy within estrogen receptor-positive breast cancer cells; the cell subset responsive to a Sox2 regulatory region (SRR2) reporter (RR cells) are significantly more tumorigenic than the reporter unresponsive (RU) cells. Here, we report that a similar phenomenon also exists in triple negative breast cancer (TNBC), with RR cells more tumorigenic than RU cells. First, examination of all 3 TNBC cell lines stably infected with the SRR2 reporter revealed the presence of a cell subset exhibiting reporter activity. Second, RU and RR cells purified by flow cytometry showed that RR cells expressed higher levels of CD44, generated more spheres in a limiting dilution mammosphere formation assay, and formed larger and more complex structures in Matrigel. Third, within the CD44 High /CD24 - tumor-initiating cell population derived from MDA-MB-231, RR cells were significantly more tumorigenic than RU cells in an in vivo SCID/Beige xenograft mouse model. Examination of 4 TNBC tumors from patients also revealed the presence of a RR cell subset, ranging from 1.1-3.8%. To conclude, we described a novel phenotypic heterogeneity within TNBC, and the SRR2 reporter responsiveness is a useful marker for identifying a highly tumorigenic cell subset within the CD44 High /CD24 - tumor-initiating cell population.