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.
Highlights
Breast cancer classification based on gene expression profile showed at least 5 distinct subtypes: luminal A, luminal B, normal breast-like, human epidermal growth factor receptor 2-positive, and triplenegative/basal-like [1]
In this study we demonstrate that IRIS overexpression (IRISOE) suppresses BRCA1 protein expression, while enhances basalbiomarkers, epithelial-to-mesenchymal transition (EMT)-inducers, stemness-enforcers expression, and the Tumor-initiating cells (TICs) phenotype all are known Triple-negative breast cancer (TNBC) cells associated events
With regard to the effect on BRCA1 expression, we recently showed that IROSE ERα function in ERα/BRCA1expressing breast cancer cells (e.g., MCF7) [40]
Summary
Breast cancer classification based on gene expression profile showed at least 5 distinct subtypes: luminal A, luminal B, normal breast-like, human epidermal growth factor receptor 2-positive, and triplenegative/basal-like [1]. TNBCs are enriched for germline BRCA1 mutations, and women who carry a BRCA1 mutation typically develop TNBCs [10]. Both BRCA1-related cancers and TNBCs show induction of the tumor-initiating cells (TICs) phenotype. Basal-like carcinomas originate from mammary stem cells and physiological progenitors within the normal female breast share immunohistochemical features with basal-like breast cancers [1, 11]
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