Cancer relapse and metastasis are major obstacles for effective treatment. One important mechanism to eliminate cancer cells is to induce apoptosis. Activation of executioner caspases is the key step in apoptosis and was considered “a point of no return”. However, in recent years, accumulating evidence has demonstrated that cells can survive executioner caspase activation in response to apoptotic stimuli through a process named anastasis. Here we show that breast cancer cells that have survived through anastasis (anastatic cells) after exposure to chemotherapeutic drugs acquire enhanced proliferation and migration. Mechanistically, cadherin 12 (CDH12) is persistently upregulated in anastatic cells and promotes breast cancer malignancy via activation of ERK and CREB. Moreover, we demonstrate that executioner caspase activation induced by chemotherapeutic drugs results in loss of DNA methylation and repressive histone modifications in the CDH12 promoter region, leading to increased CDH12 expression. Our work unveils the mechanism underlying anastasis-induced enhancement in breast cancer malignancy, offering new therapeutic targets for preventing post-chemotherapy cancer relapse and metastasis.

癌症复发和转移是有效治疗的主要障碍。消除癌细胞的一项重要机制是诱导细胞凋亡。刽子手半胱天冬酶的激活是细胞凋亡的关键步骤，被认为是“不归路”。然而，近年来，越来越多的证据表明，细胞可以通过一种名为“anastasis”的过程，在响应凋亡刺激的刽子手半胱天冬酶激活中存活下来。在这里，我们发现，在暴露于化疗药物后，通过变性存活的乳腺癌细胞（变性细胞）获得了增强的增殖和迁移。从机制上讲，钙粘蛋白 12 (CDH12) 在生长细胞中持续上调，并通过 ERK 和 CREB ​​的激活促进乳腺癌恶性肿瘤。而且，CDH12启动子区域，导致 CDH12 表达增加。我们的工作揭示了转移诱导乳腺癌恶性程度增强的机制，为预防化疗后癌症复发和转移提供了新的治疗靶点。