title: BRCA1-IRIS overexpression promotes and maintains the tumor initiating phenotype: implications for triple negative breast cancer early lesions.
abstract: 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.
authors.affiliation: Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Abhilasha
authors.initials: A
authors.lastname: Sinha
authors.affiliation: Department of Molecular Biology and Biophysics, University of Connecticut Health Center, Farmington, CT, USA.
authors.forename: Bibbin T
authors.initials: BT
authors.lastname: Paul
authors.affiliation: Department of Pathology, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Sullivan
authors.affiliation: Department of Pathology, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Hillary
authors.initials: H
authors.lastname: Sims
authors.affiliation: Medical Oncology, National Cancer Institute, Cairo University, Cairo, Egypt.
authors.forename: Ahmed
authors.initials: A
authors.lastname: El Bastawisy
authors.affiliation: Cytogenetics and Molecular Genetics, National Cancer Institute, Cairo University, Cairo, Egypt.
authors.forename: Hend F
authors.initials: HF
authors.lastname: Yousef
authors.affiliation: Virology and Immunology, National Cancer Institute, Cairo University, Cairo, Egypt.
authors.forename: Abdel-Rahman N
authors.initials: AN
authors.lastname: Zekri
authors.affiliation: Molecular Pathology and Cytogenetics, National Cancer Institute, Cairo University, Cairo, Egypt.
authors.forename: Abeer A
authors.initials: AA
authors.lastname: Bahnassy
authors.affiliation: Cancer Institute, University of Mississippi Medical Center, Jackson, MS, USA.|Department of Pathology, University of Mississippi Medical Center, Jackson, MS, USA.
authors.forename: Wael M
authors.initials: WM
authors.lastname: ElShamy
mesh_terms: D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D051927:CD24 Antigen / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D050697:Retinal Dehydrogenase / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D047368:Tumor Burden; D015854:Up-Regulation
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D014408:Biomarkers, Tumor; D051927:CD24 Antigen; C497889:CD24 protein, human; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D007527:Isoenzymes; D000080924:Aldehyde Dehydrogenase 1 Family; C510223:ALDH1A1 protein, human; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase
keywords: BRCA1-IRIS; TNBC; breast cancer; early lesion; metastasis