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

被引:30
作者
Yamashita, Nami [1 ]
Kufe, Donald [1 ]
机构
[1] Harvard Med Sch, Dana Farber Canc Inst, Boston, MA 02215 USA
基金
美国国家卫生研究院;
关键词
MUC1-C; TNBC; CSC; DNA damage resistance; immune evasion; ANTIBODY-DRUG CONJUGATE; TUMOR-INFILTRATING LYMPHOCYTES; LUNG-CANCER; SACITUZUMAB GOVITECAN; ONCOPROTEIN FUNCTIONS; SIGNALING PATHWAYS; IMMUNE EVASION; DOUBLE-BLIND; C-SRC; PROTEIN;
D O I
10.3390/ijms23158219
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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页数:14
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