PINCH-1 is a cytoplasmic component of the cell-extracellular matrix (ECM) adhesion machine that is frequently overexpressed in cancer. The functions and mechanism of PINCH-1 in cancer, however, remain to be determined. Here, we show that PINCH-1 interacts with myoferlin, a transmembrane protein that is critical for cancer progression. High expression of both PINCH-1 and myoferlin correlates with poor clinical outcome in human breast cancer patients. Ablation of PINCH-1 from breast cancer cells diminished myoferlin level and suppressed breast cancer cell proliferation, migration, and endothelial cell tube formation in vitro and breast tumor growth, angiogenesis and metastasis in vivo. Mechanistically, PINCH-1 controls myoferlin level through its interaction with myoferlin and regulation of its ubiquitination and proteasome-dependent degradation. Functionally, re-expression of PINCH-1, but not that of a myoferlin-binding defectiveΔLIM2 mutant, effectively reversed the inhibition of myoferlin expression and breast cancer progression induced by loss of PINCH-1. Finally, restoration of myoferlin expression was sufficient to reverse PINCH-1-deficiency induced inhibition on breast cancer progression. These results reveal a PINCH-1-myoferlin signaling axis that is critical for breast cancer progression and suggest a new strategy for therapeutic control of breast cancer.

PINCH-1 是细胞-细胞外基质 (ECM) 粘附机器的细胞质成分，在癌症中经常过度表达。然而，PINCH-1在癌症中的功能和机制仍有待确定。在这里，我们展示了 PINCH-1 与肌铁蛋白相互作用，肌铁蛋白是一种对癌症进展至关重要的跨膜蛋白。PINCH-1 和肌铁蛋白的高表达与人类乳腺癌患者的不良临床结果相关。从乳腺癌细胞中去除 PINCH-1 可降低肌铁蛋白水平并抑制体外乳腺癌细胞增殖、迁移和内皮细胞管形成以及体内乳腺肿瘤生长、血管生成和转移。从机制上讲，PINCH-1 通过其与肌铁蛋白的相互作用以及调节其泛素化和蛋白酶体依赖性降解来控制肌铁蛋白水平。在功能上，PINCH-1 的重新表达，而不是肌铁蛋白结合缺陷的ΔLIM2 突变体的重新表达，有效地逆转了由 PINCH-1 缺失诱导的肌铁蛋白表达和乳腺癌进展的抑制。最后，肌铁蛋白表达的恢复足以逆转 PINCH-1 缺陷诱导的乳腺癌进展抑制。这些结果揭示了一个对乳腺癌进展至关重要的 PINCH-1-myoferlin 信号轴，并提出了一种治疗控制乳腺癌的新策略。肌铁蛋白表达的恢复足以逆转 PINCH-1 缺陷诱导的乳腺癌进展抑制。这些结果揭示了一个对乳腺癌进展至关重要的 PINCH-1-myoferlin 信号轴，并提出了一种治疗控制乳腺癌的新策略。肌铁蛋白表达的恢复足以逆转 PINCH-1 缺陷诱导的乳腺癌进展抑制。这些结果揭示了一个对乳腺癌进展至关重要的 PINCH-1-myoferlin 信号轴，并提出了一种治疗控制乳腺癌的新策略。