Targeting Mdmx to treat breast cancers with wild-type p53.
Targeting Mdmx to treat breast cancers with wild-type p53.
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DOI：
10.1038/cddis.2015.173
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发表时间：
2015-07-16
影响因子：
9
通讯作者：
Haupt Y
中科院分区：
文献类型：
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作者：
Haupt S;Buckley D;Pang JM;Panimaya J;Paul PJ;Gamell C;Takano EA;Lee YY;Hiddingh S;Rogers TM;Teunisse AF;Herold MJ;Marine JC;Fox SB;Jochemsen A;Haupt Y
肿瘤抑制因子 p53 的功能在癌症中普遍受到损害。它是人类癌症中最常见的突变基因（已综述）。在 p53 未突变的情况下，替代调节途径会使其肿瘤抑制功能失活。这主要是通过提高 p53 关键抑制剂的表达来实现：Mdm2 或 Mdmx（也称为 Mdm4）（已审查）。在乳腺癌 (BrCa) 中，不同亚型之间 p53 突变的频率存在显着差异，基底样 BrCas 具有高频率的 p53 突变，而管腔 BrCas 通常表达野生型 (wt) p53。在这里，我们发现 Mdmx 在正常乳腺上皮细胞中出乎意料地高表达，并且其表达在大多数管腔 BrCas 中进一步升高，而 p53 表达通常较低，与 wt p53 状态一致。管腔 BrCa MCF-7 细胞中 Mdmx 的诱导敲低 (KD) 以 p53 依赖性方式阻碍这些细胞在培养物中的生长。重要的是，在预防模型和治疗模型中，原位异种移植物中 Mdmx 的 KD 导致与延长存活相关的生长抑制。 Mdmx KD 引起的生长障碍与细胞衰老有关。 Mdmx KD 的生长抑制能力在表达 wt p53 的额外管腔 BrCa 细胞系 MPE600 中得到重现。此外，Mdmx KD的生长抑制能力也在wt p53基底样细胞系SKBR7系中得到证实。这些结果确定了表达 BrCas 的 wt p53 在一系列亚型中的 Mdmx 生长依赖性。根据我们的研究结果，我们提出 Mdmx 靶向是治疗携带 wt p53 的 BrCas 的一种有吸引力的策略。
The function of the tumor suppressor p53 is universally compromised in cancers. It is the most frequently mutated gene in human cancers (reviewed). In cases where p53 is not mutated, alternative regulatory pathways inactivate its tumor suppressive functions. This is primarily achieved through elevation in the expression of the key inhibitors of p53: Mdm2 or Mdmx (also called Mdm4) (reviewed). In breast cancer (BrCa), the frequency of p53 mutations varies markedly between the different subtypes, with basal-like BrCas bearing a high frequency of p53 mutations, whereas luminal BrCas generally express wild-type (wt) p53. Here we show that Mdmx is unexpectedly highly expressed in normal breast epithelial cells and its expression is further elevated in most luminal BrCas, whereas p53 expression is generally low, consistent with wt p53 status. Inducible knockdown (KD) of Mdmx in luminal BrCa MCF-7 cells impedes the growth of these cells in culture, in a p53-dependent manner. Importantly, KD of Mdmx in orthotopic xenograft transplants resulted in growth inhibition associated with prolonged survival, both in a preventative model and also in a treatment model. Growth impediment in response to Mdmx KD was associated with cellular senescence. The growth inhibitory capacity of Mdmx KD was recapitulated in an additional luminal BrCa cell line MPE600, which expresses wt p53. Further, the growth inhibitory capacity of Mdmx KD was also demonstrated in the wt p53 basal-like cell line SKBR7 line. These results identify Mdmx growth dependency in wt p53 expressing BrCas, across a range of subtypes. Based on our findings, we propose that Mdmx targeting is an attractive strategy for treating BrCas harboring wt p53.