BRCA1-IRIS overexpression promotes and maintains the tumor initiating phenotype: implications for triple negative breast cancer early lesions
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Abhilasha Sinha1,*, Bibbin T. Paul2,*, Lisa M. Sullivan3, Hillary Sims3, Ahmed El Bastawisy4, Hend F. Yousef5, Abdel-Rahman N. Zekri6, Abeer A. Bahnassy7, Wael M. ElShamy1,3
1Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA
2Department of Molecular Biology and Biophysics, University of Connecticut Health Center, Farmington, CT, USA
3Department of Pathology, University of Mississippi Medical Center, Jackson, MS, USA
4Medical Oncology, National Cancer Institute, Cairo University, Cairo, Egypt
5Cytogenetics and Molecular Genetics, National Cancer Institute, Cairo University, Cairo, Egypt
6Virology and Immunology, National Cancer Institute, Cairo University, Cairo, Egypt
7Molecular Pathology and Cytogenetics, National Cancer Institute, Cairo University, Cairo, Egypt
*These authors have contributed equally to this work
Wael M. ElShamy, email: [email protected]
Keywords: breast cancer, BRCA1-IRIS, metastasis, early lesion, TNBC
Received: September 27, 2016 Accepted: December 13, 2016 Published: December 29, 2016
Tumor-initiating cells (TICs) are cancer cells endowed with self-renewal, multi-lineage differentiation, increased chemo-resistance, and in breast cancers the CD44+/CD24-/ALDH1+ phenotype. Triple negative breast cancers show lack of BRCA1 expression in addition to enhanced basal, epithelial-to-mesenchymal transition (EMT), and TIC phenotypes. BRCA1-IRIS (hereafter IRIS) is an oncogene produced by the alternative usage of the BRCA1 locus. IRIS is involved in induction of replication, transcription of selected oncogenes, and promoting breast cancer cells aggressiveness. Here, we demonstrate that IRIS overexpression (IRISOE) promotes TNBCs through suppressing BRCA1 expression, enhancing basal-biomarkers, EMT-inducers, and stemness-enforcers expression. IRISOE also activates the TIC phenotype in TNBC cells through elevating CD44 and ALDH1 expression/activity and preventing CD24 surface presentation by activating the internalization pathway EGFR→c-Src→cortactin. We show that the intrinsic sensitivity to an anti-CD24 cross-linking antibody-induced cell death in membranous CD24 expressing/luminal A cells could be acquired in cytoplasmic CD24 expressing IRISOE TNBC/TIC cells through IRIS silencing or inactivation. We show that fewer IRISOE TNBC/TICs cells form large tumors composed of TICs, resembling TNBCs early lesions in patients that contain metastatic precursors capable of disseminating and metastasizing at an early stage of the disease. IRIS-inhibitory peptide killed these IRISOE TNBC/TICs, in vivo and prevented their dissemination and metastasis. We propose IRIS inactivation could be pursued to prevent dissemination and metastasis from early TNBC tumor lesions in patients.
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