Stratification and therapeutic potential of PML in metastatic breast cancer
Stratification and therapeutic potential of PML in metastatic breast cancer
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DOI：
10.1038/ncomms12595
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发表时间：
2016-08-01
影响因子：
16.6
通讯作者：
Carracedo, Arkaitz
中科院分区：
文献类型：
--
作者：
Martin-Martin, Natalia;Piva, Marco;Carracedo, Arkaitz
患者分层对乳腺癌靶向治疗的成功起到了重要作用。然而，转移性乳腺癌的分子基础及其治疗的脆弱性仍然知之甚少。在这里，我们展示了PML是侵袭性乳腺癌的一个新靶点。乳腺肿瘤的侵袭性和转移性特征的获得伴随着PML表达的升高和对其抑制的敏感性增强。有趣的是，我们发现STAT3至少在一定程度上是乳腺癌中PML转录上调的原因。此外，PML靶向阻碍了乳腺癌的启动和转移种植。从机制上讲，这种生物学活性依赖于干细胞基因SOX9的调节，通过PML与其启动子区域的相互作用。总之，我们确定了一种维持乳腺癌侵袭性的新途径，可以与基于PML的分层相结合用于治疗。
Patient stratification has been instrumental for the success of targeted therapies in breast cancer. However, the molecular basis of metastatic breast cancer and its therapeutic vulnerabilities remain poorly understood. Here we show that PML is a novel target in aggressive breast cancer. The acquisition of aggressiveness and metastatic features in breast tumours is accompanied by the elevated PML expression and enhanced sensitivity to its inhibition. Interestingly, we find that STAT3 is responsible, at least in part, for the transcriptional upregulation of PML in breast cancer. Moreover, PML targeting hampers breast cancer initiation and metastatic seeding. Mechanistically, this biological activity relies on the regulation of the stem cell gene SOX9 through interaction of PML with its promoter region. Altogether, we identify a novel pathway sustaining breast cancer aggressiveness that can be therapeutically exploited in combination with PML-based stratification.