RB1 and p53 at the crossroad of EMT and triple negative breast cancer
RB1 and p53 at the crossroad of EMT and triple negative breast cancer
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DOI：
10.4161/cc.10.10.15703
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发表时间：
2011-05-15
期刊：
影响因子：
4.3
通讯作者：
Zacksenhaus, Eldad
中科院分区：
文献类型：
--
作者：
Jiang, Zhe;Jones, Robert;Zacksenhaus, Eldad
三阴性乳腺癌（TNBC）是一种异质性疾病，包括基底样和低克劳丁肿瘤。低claudin的肿瘤富含与上皮-间质转化（EMT）相关的特征，可能与肿瘤起始细胞有关。原发性tnbc对常规化疗反应相对较好；然而，转移性疾病实际上是无法治愈的。因此，人们对确定TNBC的特定治疗靶点非常感兴趣。肿瘤抑制因子RB1在基底样乳腺癌中经常缺失。为了测试RB1基因缺失在BC中的致病作用及其对特定亚型的影响，我们在乳腺干细胞/双能祖细胞中删除了小鼠Rb。这导致了包括TNBC在内的多种乳腺肿瘤，后者的一个子集包含p53突变，并表现出基底样BC或EMT的特征。乳腺干/双能祖细胞Rb和p53联合突变诱导EMT型肿瘤。在这里，我们回顾了我们的发现以及其他将Rb和p53与TNBC中的EMT联系起来的发现。此外，我们讨论了如何通过理解这种回路及其脆弱性，我们可以确定新的治疗TNBC的方法。
Triple negative breast cancer (TNBC) is a heterogeneous disease that includes Basal-like and Claudin-low tumors. The Claudin-low tumors are enriched for features associated with epithelial-to-mesenchymal transition (EMT) and possibly for tumor initiating cells. Primary TNBCs respond relatively well to conventional chemotherapy; however, metastatic disease is virtually incurable. Thus, there is a great interest in identifying specific therapeutic targets for TNBC. The tumor suppressor RB1 is frequently lost in Basal-like breast cancer. To test for a causative role of RB1 gene loss in BC and for its effect on specific subtypes, we deleted mouse Rb in mammary stem/bipotent progenitor cells. This led to diverse mammary tumors including TNBC, with a subset of the latter containing p53 mutations and exhibiting features of Basal-like BC or EMT. Combined mutation of Rb and p53 in mammary stem/bipotent progenitors induced EMT type tumors. Here, we review our findings and those of others, which connect Rb and p53 to EMT in TNBC. Furthermore, we discuss how by understanding this circuit and its vulnerabilities, we may identify novel therapy for TNBC.