Restraining FOXO3-dependent transcriptional BMF activation underpins tumour growth and metastasis of E-cadherin-negative breast cancer
Restraining FOXO3-dependent transcriptional BMF activation underpins tumour growth and metastasis of E-cadherin-negative breast cancer
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DOI：
10.1038/cdd.2016.33
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发表时间：
2016-09-01
影响因子：
12.4
通讯作者：
Derksen, P. W. B.
中科院分区：
文献类型：
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作者：
Hornsveld, M.;Tenhagen, M.;Derksen, P. W. B.
细胞粘附的丧失通过获得锚定独立性（也称为对失巢凋亡的抵抗）导致乳腺癌的进展。尽管E-钙粘蛋白的失活对于获得失巢凋亡抗性是必不可少的，但仍不清楚转移性乳腺癌细胞如何在没有E-钙粘蛋白依赖性细胞粘附的情况下抵消凋亡的诱导。我们在这里报告，在乳腺癌细胞中的E-钙粘蛋白失活诱导PI 3 K/AKT依赖性FOXO 3抑制和确定FOXO 3作为一种新的和直接的促凋亡蛋白BMF的转录激活剂。因此，E-钙粘蛋白阴性乳腺在转移到锚定独立性后不能上调BMF，导致失巢凋亡抵抗。相反，在E-钙粘蛋白阴性转移性乳腺癌细胞中表达BMF足以抑制小鼠中的肿瘤生长和传播。总之，我们已经确定了BMF的抑制作为支撑失巢凋亡抵抗和E-钙粘蛋白缺陷转移性乳腺癌的肿瘤扩散的主要线索。
Loss of cellular adhesion leads to the progression of breast cancer through acquisition of anchorage independence, also known as resistance to anoikis. Although inactivation of E-cadherin is essential for acquisition of anoikis resistance, it has remained unclear how metastatic breast cancer cells counterbalance the induction of apoptosis without E-cadherin-dependent cellular adhesion. We report here that E-cadherin inactivation in breast cancer cells induces PI3K/AKT-dependent FOXO3 inhibition and identify FOXO3 as a novel and direct transcriptional activator of the pro-apoptotic protein BMF. As a result, E-cadherin-negative breast fail to upregulate BMF upon transfer to anchorage independence, leading to anoikis resistance. Conversely, expression of BMF in E-cadherin-negative metastatic breast cancer cells is sufficient to inhibit tumour growth and dissemination in mice. In conclusion, we have identified repression of BMF as a major cue that underpins anoikis resistance and tumour dissemination in E-cadherin-deficient metastatic breast cancer.