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.

The role of BRCA1-IRIS in the development and progression of triple negative breast cancers in Egypt: possible link to disease early lesion

“…Injecting fewer rather than large number of such cells displayed increased capabilities to generate tumors, CTCs and DTCs, clearly support BRCA1-IRIS overexpressing TNBC cells early dissemination [14]. In the current study, we aimed at determining the prevalence of BRCA1-IRIS overexpression in a cohort of Egyptian patients with invasive breast cancers, defining the possible effect of BRCA1-IRIS overexpression on TNBCs clinical and biological behavior compared to the non-TNBCs, and whether its overexpression is associated with dissemination from early TNBC lesions.…”

BRCA1—No Matter How You Splice It

“…The BRCA1-IRIS promoter is active in the G0 phase in some cell lines and the transcript can be detected in both the G 0 and S phases during the cell cycle (44). Interestingly, BRCA1-IRIS overexpression is associated with the absence of full-length BRCA1 expression (44,62). BRCA1-IRIS is highly expressed in some breast and ovarian cancer cell lines, especially in the HCC1937 cell line, which does not express any full-length BRCA1 transcript because of BRCA1 genetic mutations (44,63,64).…”

“…In patients with triple-negative breast cancer (TNBC), high expression of BRCA1-IRIS correlates with aggressive clinical behavior of breast cancer, including lymph node metastasis, local recurrence, distant metastasis, and decreased survival (66,67). Both in vitro cell studies and in vivo xenograft mice models demonstrate that BRCA1-IRIS overexpression promotes TNBC tumor formation, invasion, and migration (62,(66)(67)(68)(69)(70)(71). The proposed mechanism is that BRCA1-IRIS may increase DNA replication and cell proliferation (44), induce transcription of oncogenes cyclin D1 and EGFR (69, 71, 72), suppress full-length BRCA1 expression (62), activate WIP1 phosphatase (73,74), enhance EMT (epithelialmesenchymal transition), upregulate transcription factors associated with stemness, and activate the tumor-initiating cells (TIC) phenotype in TNBC cells (62).…”

“…Both in vitro cell studies and in vivo xenograft mice models demonstrate that BRCA1-IRIS overexpression promotes TNBC tumor formation, invasion, and migration (62,(66)(67)(68)(69)(70)(71). The proposed mechanism is that BRCA1-IRIS may increase DNA replication and cell proliferation (44), induce transcription of oncogenes cyclin D1 and EGFR (69, 71, 72), suppress full-length BRCA1 expression (62), activate WIP1 phosphatase (73,74), enhance EMT (epithelialmesenchymal transition), upregulate transcription factors associated with stemness, and activate the tumor-initiating cells (TIC) phenotype in TNBC cells (62). BRCA1-IRIS overexpression can also promote paclitaxel resistance in TNBC breast cancers, partly by activating an autocrine signaling loop of EGF/EGFR-ErbB2 and NRG1/ErbB2-ErbB3 (71).…”

“…Potentially, BRCA1-IRIS inactivation may also be a therapeutic strategy in aggressive breast tumors (62,66). Studies in TNBCs showed that an IRIS-inhibitory peptide can inhibit TNBC progression (62,71) and sensitize TNBC cells to low paclitaxel concentrations (71) both in vitro and in vivo.…”