Loss of RasGAP Tumor Suppressors Underlies the Aggressive Nature of Luminal B Breast Cancers.
Loss of RasGAP Tumor Suppressors Underlies the Aggressive Nature of Luminal B Breast Cancers.
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DOI：
10.1158/2159-8290.cd-16-0520
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发表时间：
2017-03
期刊：
影响因子：
28.2
通讯作者：
Cichowski K
中科院分区：
文献类型：
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作者：
Olsen SN;Wronski A;Castaño Z;Dake B;Malone C;De Raedt T;Enos M;DeRose YS;Zhou W;Guerra S;Loda M;Welm A;Partridge AH;McAllister SS;Kuperwasser C;Cichowski K
腔内乳腺癌通常是雌激素受体阳性，通常预后最好。然而，腔内肿瘤的一个子集，即腔B癌，经常转移和复发。不幸的是，推动其进展的因果事件尚不清楚，因此很难确定哪些人可能复发并应接受逐步治疗。在这里，我们确定了一种双功能的RasGAP肿瘤抑制因子，它在几乎50%的腔性B肿瘤中丢失。此外，我们发现在最具侵袭性的腔性恶性肿瘤中，两个RasGAP基因同时失活。重要的是，这些基因通过不同的结构域协同调节RAS和NF-kappaB两条主要的致癌途径，并且当失活时驱动体内肿瘤的转移。最后，虽然RAS的协同作用推动了肿瘤的侵袭，但NF-κB的激活触发了子宫内膜上皮细胞的转移，并且是转移所必需的。总而言之，这些研究揭示了对管腔B肿瘤发病机制的重要机制洞察，并提供了可能指导治疗决策的功能相关预后生物标志物。
Luminal breast cancers are typically estrogen receptor positive and generally have the best prognosis. However, a subset of luminal tumors, namely luminal B cancers, frequently metastasize and recur. Unfortunately, the causal events that drive their progression are unknown and therefore it is difficult to identify individuals who are likely to relapse and should receive escalated treatment. Here we identify a bi-functional RasGAP tumor suppressor that is lost in almost 50% of luminal B tumors. Moreover, we show that two RasGAP genes are concomitantly inactivated in the most aggressive luminal malignancies. Importantly, these genes cooperatively regulate two major oncogenic pathways, Ras and NF-kappa B through distinct domains, and when inactivated drive the metastasis of luminal tumors in vivo. Finally, while the cooperative effects on Ras drive invasion, NF-κB activation triggers EMT and is required for metastasis. Collectively, these studies reveal important mechanistic insight into the pathogenesis of luminal B tumors and provide functionally relevant prognostic biomarkers that may guide treatment decisions.