Cdh1 and Pik3ca Mutations Cooperate to Induce Immune-Related Invasive Lobular Carcinoma of the Breast.
Cdh1 and Pik3ca Mutations Cooperate to Induce Immune-Related Invasive Lobular Carcinoma of the Breast.
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DOI：
10.1016/j.celrep.2018.09.056
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发表时间：
2018-10-16
期刊：
影响因子：
8.8
通讯作者：
Egan SE
中科院分区：
文献类型：
--
作者：
An Y;Adams JR;Hollern DP;Zhao A;Chang SG;Gams MS;Chung PED;He X;Jangra R;Shah JS;Yang J;Beck LA;Raghuram N;Kozma KJ;Loch AJ;Wang W;Fan C;Done SJ;Zacksenhaus E;Guidos CJ;Perou CM;Egan SE
CDH1和PIK3CA是乳腺浸润性小叶癌（ILC）中最常见的两个突变基因。转录谱分析已经确定了ILC的分子亚型，其中免疫相关（IR）亚型与淋巴细胞和巨噬细胞浸润相关的基因表达相关。在这里，我们报道了Cdh1的缺失，以及转基因小鼠乳腺上皮中Pik3ca的激活，导致免疫细胞浸润的ir - ilc样肿瘤的形成，以及与t调节（Treg）细胞信号传导相关的基因表达和可靶向的免疫检查点途径的激活。有趣的是，这些肿瘤在培养中表现出增强的Rac1和Yap依赖性转录和信号传导，以及对PI3K、Rac1和Yap抑制剂的敏感性。最后，通过大量细胞术对对照小鼠乳腺和IR-ILC肿瘤进行高维免疫表型分析显示，髓细胞和淋巴细胞群体与免疫抑制和衰竭相关的显著改变，突出了通过免疫检查点调节剂进行治疗干预的潜力。An等人基于人类浸润性小叶癌（ILC）中两个最易突变的基因描述了乳腺浸润性小叶癌（ILC）小鼠模型的发展和特征。该模型类似于免疫相关的ILC，显示出与免疫抑制和衰竭一致的髓细胞和T细胞改变，并代表了治疗的平台。
CDH1 and PIK3CA are the two most frequently mutated genes in invasive lobular carcinoma (ILC) of the breast. Transcription profiling has identified molecular subtypes for ILC, one of which, immune-related (IR), is associated with gene expression linked to lymphocyte and macrophage infiltration. Here, we report that deletion of Cdh1, together with activation of Pik3ca in mammary epithelium of genetically modified mice, leads to formation of IR-ILC-like tumors with immune cell infiltration, as well as gene expression linked to T-regulatory (Treg) cell signaling and activation of targetable immune checkpoint pathways. Interestingly, these tumors show enhanced Rac1-and Yap-dependent transcription and signaling, as well as sensitivity to PI3K, Rac1, and Yap inhibitors in culture. Finally, high-dimensional immunophenotyping in control mouse mammary gland and IR-ILC tumors by mass cytometry shows dramatic alterations in myeloid and lymphoid populations associated with immune suppression and exhaustion, highlighting the potential for therapeutic intervention via immune checkpoint regulators. An et al. describe the development and characterization of a mouse model for invasive lobular carcinoma (ILC) of the breast based on the two most mutated genes in human ILC. This model is analogous to immune-related ILC, shows myeloid and T cell alterations consistent with immune suppression and exhaustion, and represents a platform for therapeutics.
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