Addiction of Cancer Stem Cells to MUC1-C in Triple-Negative Breast Cancer Progression

Abstract

Triple-negative breast cancer (TNBC) is an aggressive malignancy with limited treatment options. TNBC progression is associated with expansion of cancer stem cells (CSCs). Few insights are available regarding druggable targets that drive the TNBC CSC state. This review summarizes the literature on TNBC CSCs and the compelling evidence that they are addicted to the MUC1-C transmembrane protein. In normal epithelia, MUC1-C is activated by loss of homeostasis and induces reversible wound-healing responses of inflammation and repair. However, in settings of chronic inflammation, MUC1-C promotes carcinogenesis. MUC1-C induces EMT, epigenetic reprogramming and chromatin remodeling in TNBC CSCs, which are dependent on MUC1-C for self-renewal and tumorigenicity. MUC1-C-induced lineage plasticity in TNBC CSCs confers DNA damage resistance and immune evasion by chronic activation of inflammatory pathways and global changes in chromatin architecture. Of therapeutic significance, an antibody generated against the MUC1-C extracellular domain has been advanced in a clinical trial of anti-MUC1-C CAR T cells and in IND-enabling studies for development as an antibody-drug conjugate (ADC). Agents targeting the MUC1-C cytoplasmic domain have also entered the clinic and are undergoing further development as candidates for advancing TNBC treatment. Eliminating TNBC CSCs will be necessary for curing this recalcitrant cancer and MUC1-C represents a promising druggable target for achieving that goal.

Keywords: CSC; DNA damage resistance; MUC1-C; TNBC; immune evasion.

Figure 1

MUC1-C integrates activation of TNBC cell membrane signaling with the induction of EMT, lineage plasticity, DNA damage resistance and immune evasion. Activation of MUC1-C by loss of homeostasis is associated with the formation of homodimers that interact with EGFR and other RTKs at the cell membrane. MUC1-C homodimers are internalized by endocytic trafficking. Intracellular MUC1-C homodimers are transported to the mitochondrial outer membrane, where they block cell death. MUC1-C homodimers are also imported to the nucleus by importin-β and interactions with the nuclear pore complex (NPC). In the nucleus, MUC1-C interacts with TFs, such as WNT/β-catenin/TCF4, NF-κB, NOTCH and MYC, to drive EMT, epigenetic reprogramming and the cancer stem cell (CSC) state, which contribute to lineage plasticity, DNA damage resistance and immune evasion. Antibodies generated against the MUC1-C extracellular domain are being developed for CAR T cell and antibody–drug conjugate (ADC) immunotherapeutics. Targeting the MUC1-C cytoplasmic domain with the GO-203 inhibitor blocks MUC1-C homodimerization, nuclear import and function. Figure modified from [57,58].

Figure 2

Targeting the MUC1-C extracellular domain. MUC1-C consists of a 58 aa extracellular domain (ED), 28 aa transmembrane domain (TM) and a 72 aa cytoplasmic domain (CD). The MUC1-C ED includes α3 and α4 helices that are exposed with MUC1-C activation and are targets for monoclonal antibodies (MAbs). MAb 3D1 has been generated against the α3 helix and is under development as CAR T cell and ADC approaches. Figure modified from [58,120].

Figure 3

MUC1-C cytoplasmic domain interacts with diverse effectors of the CSC state. The MUC1-C CD (72 aa) is an intrinsically disordered protein that functions as a node in integrating multiple signaling pathways that promote the CSC state. MUC1-CD includes a CQC motif that is (i) a sensor of increases in ROS, (ii) necessary for the formation of MUC1-C homodimers and (iii) a target for the GO-203 inhibitor. The MUC1-CD CQC motif confers binding to MYC. Shown are tyrosine phosphorylation sites that function as motifs for interactions with PI3K (pYHPM) and GRB2 (pYTNP) in activating the AKT and ERK pathways, respectively. Also shown are potential consensus SH2 binding motifs for interactions with SHC (pYPTY) and PLCγ1 (pYVPP). In addition, MUC1-CD interacts directly with proinflammatory TFs, such as NF-κB and STAT3, and the WNT pathway effectors, β-catenin and TCF4, that are associated with driving the CSC state. Highlighted is the SAGNGGSSLS or SER-rich motif (SRM) that functions as a binding region for STAT3, β-catenin and TCF4. Figure modified from [57,98].