High Myc expression and transcription activity underlies intra-tumoral heterogeneity in triple-negative breast cancer
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Nidhi Gupta1,*, Karen Jung2,*, Chengsheng Wu1, Abdulraheem Alshareef1, Hind Alqahtani1, Sambasivarao Damaraju1,3, John R. Mackey2,3, Sunita Ghosh2,3, Siham Sabri4, Bassam S. Abdulkarim4, Gilbert Bigras1, Raymond Lai1,2,5
1 Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada
2Department of Oncology, University of Alberta, Edmonton, Alberta, Canada
3Cross Cancer Institute, Alberta Heath Services, Edmonton, Alberta, Canada
4Department of Oncology, McGill University, Montreal, Quebec, Canada
5DynaLIFEDx Medical Laboratories, Edmonton, Alberta, Canada
*These authors contributed equally to this work
Raymond Lai, email: firstname.lastname@example.org
Keywords: triple-negative breast cancer, Myc, transcription activity, intra-tumoral heterogeneity, MAPK/ERK pathway
Received: September 13, 2016 Accepted: February 21, 2017 Published: March 03, 2017
We have previously identified a novel intra-tumoral dichotomy in triple-negative breast cancer (TNBC) based on the differential responsiveness to a reporter containing the Sox2 regulatory region-2 (SRR2), with reporter responsive (RR) cells being more stem-like than reporter unresponsive (RU) cells. Using bioinformatics, we profiled the protein-DNA binding motifs of SRR2 and identified Myc as one of the potential transcription factors driving SRR2 activity. In support of its role, Myc was found to be highly expressed in RR cells as compared to RU cells. Enforced expression of MYC in RU cells resulted in a significant increase in SRR2 activity, Myc-DNA binding, proportion of cellsexpressing CD44+/CD24–, chemoresistance and mammosphere formation. Knockdown of Myc using siRNA in RR cells led to the opposite effects. We also found evidence that the relatively high ERK activation in RR cells contributes to their high expression of Myc and stem-like features. Using confocal microscopy and patient samples, we found a co-localization between Myc and CD44 in the same cell population. Lastly, a high proportion of Myc-positive cells in tumors significantly correlated with a short patient survival. In conclusion, inhibition of the MAPK/ERK/Myc axis may be an effective approach in eliminating stem-like cells in TNBC.
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