Abstract
Triple negative breast cancer (TNBC) patients have high risk of recurrence and metastasis, and current treatment options remain limited. Cancer stem-like cells (CSCs) have been linked to cancer initiation, progression and chemotherapy resistance. Notch signaling is a key pathway regulating TNBC CSC survival. Treatment of TNBC with PI3K or mTORC1/2 inhibitors results in drug-resistant, Notch-dependent CSC. However, downstream mechanisms and potentially druggable Notch effectors in TNBC CSCs are largely unknown. We studied the role of the AKT pathway and mitochondrial metabolism downstream of Notch signaling in TNBC CSC from cell lines representative of different TNBC molecular subtypes as well as a novel patient-derived model. We demonstrate that exposure of TNBC cells to recombinant Notch ligand Jagged1 leads to rapid AKT phosphorylation in a Notch1-dependent but RBP-Jκ independent fashion. This requires mTOR and IKKα. Jagged1 also stimulates mitochondrial respiration and fermentation in an AKT- and IKK-dependent fashion. Notch1 co-localizes with mitochondria in TNBC cells. Pharmacological inhibition of Notch cleavage by gamma secretase inhibitor PF-03084014 in combination with AKT inhibitor MK-2206 or IKK-targeted NF-κB inhibitor Bay11-7082 blocks secondary mammosphere formation from sorted CD90hi or CD44+CD24low (CSCs) cells. A TNBC patient-derived model gave comparable results. Besides mitochondrial oxidative metabolism, Jagged1 also triggers nuclear, NF-κB-dependent transcription of anti-apoptotic gene cIAP-2. This requires recruitment of Notch1, IKKα and NF-κB to the cIAP-2 promoter. Our observations support a model where Jagged1 triggers IKKα-dependent, mitochondrial and nuclear Notch1 signals that stimulate AKT phosphorylation, oxidative metabolism and transcription of survival genes in PTEN wild-type TNBC cells. These data suggest that combination treatments targeting the intersection of the Notch, AKT and NF-κB pathways have potential therapeutic applications against CSCs in TNBC cases with Notch1 and wild-type PTEN expression.
Highlights
Triple negative breast cancer (TNBC) is a heterogeneous group of clinically aggressive breast cancers, designated as pathologically negative for estrogen receptor (ER−), progesterone receptor (PR−), and human epidermal growth factor receptor 2 amplification (HER2−)
In TNBC, resistance to PI3K or mTORC1/2 inhibitors is mediated by Notch through unknown mechanisms [6]
Initial experiments were performed in the co-culture system we used to dissect the crosstalk of Notch1 with ERα [37]
Summary
Triple negative breast cancer (TNBC) is a heterogeneous group of clinically aggressive breast cancers, designated as pathologically negative for estrogen receptor (ER−), progesterone receptor (PR−), and human epidermal growth factor receptor 2 amplification (HER2−). Increasing evidence suggests that cancer stem-like cells (CSCs), present at diagnosis or evolved during treatment through epithelial-mesenchymal transition (EMT) and/or clonal selection are the driving force of tumorigenesis, chemo/radioresistance and metastatic spread. There is strong evidence for the involvement of Notch signaling in TNBC [2,3,4,5,6]. The basal-like 1 (BL1) and mesenchymal stem-like (MSL, merged with the Mesenchymal subtype) subtypes of TNBC are characterized by dysregulation of Notch modulators Lunatic Fringe (LFng) or Manic Fringe (MFng) and elevated expression of Notch1 [14,15,16,17]. There is strong evidence supporting key roles of different Notch paralogs in breast CSCs [18,19,20,21,22,23]. The downstream mechanisms and potentially druggable Notch effectors in TNBC CSCs are largely unknown
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