Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Int J Mol Sci. 2022 Jul 26;23(15):8219. doi: 10.3390/ijms23158219.
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.
三阴性乳腺癌（TNBC）是一种侵袭性恶性肿瘤，治疗选择有限。TNBC 的进展与癌症干细胞（CSC）的扩张有关。关于驱动 TNBC CSC 状态的可用药靶标，目前还知之甚少。这篇综述总结了关于 TNBC CSC 的文献，以及令人信服的证据表明它们依赖于跨膜蛋白 MUC1-C。在正常上皮中，MUC1-C 通过失去内稳态而被激活，并诱导炎症和修复的可逆伤口愈合反应。然而，在慢性炎症的情况下，MUC1-C 促进了癌症的发生。MUC1-C 在 TNBC CSC 中诱导 EMT、表观遗传重编程和染色质重塑，这些过程依赖于 MUC1-C 来实现自我更新和致瘤性。MUC1-C 诱导 TNBC CSC 中的谱系可塑性赋予了 DNA 损伤抗性和免疫逃逸，这是通过慢性激活炎症途径和染色质结构的全局变化来实现的。具有治疗意义的是，针对 MUC1-C 细胞外结构域的抗体已在针对 MUC1-C 的 CAR T 细胞的临床试验中以及作为抗体药物偶联物（ADC）开发的 IND 启用研究中得到推进。针对 MUC1-C 细胞质结构域的药物也已进入临床，并正在进一步开发，作为推进 TNBC 治疗的候选药物。消除 TNBC CSC 将是治愈这种难治性癌症的必要条件，而 MUC1-C 代表了一个有前途的可用药靶，有望实现这一目标。
