Notch activation, which is associated with basal-like breast cancer (BLBC), normally directs tissue patterning, suggesting that it may shape the tumor microenvironment. Here, we show that Notch in tumor cells regulates the expression of two powerful proinflammatory cytokines, IL1β and CCL2, and the recruitment of tumor-associated macrophages (TAM). Notch also regulates TGFβ-mediated activation of tumor cells by TAMs, closing a Notch-dependent paracrine signaling loop between these two cell types. We use a mouse model in which Notch can be regulated in spontaneous mammary carcinoma to confirm that IL1β and CCL2 production, and macrophage recruitment are Notch-dependent. In human disease, expression array analyses demonstrate a striking association between Notch activation, IL1β and CCL2 production, macrophage infiltration, and BLBC. These findings place Notch at the nexus of a vicious cycle of macrophage infiltration and amplified cytokine secretion and provide immunotherapeutic opportunities in BLBC.

Significance: BLBC is aggressive and has an unmet need for effective targeted treatment. Our data highlight immunotherapeutic opportunities in Notch-activated BLBC. Effective IL1β and CCL2 antagonists are currently in clinical review to treat benign inflammatory disease, and their transition to the cancer clinic could have a rapid impact. Cancer Discov; 7(11); 1320–35. ©2017 AACR.

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与基底样乳腺癌（BLBC）相关的Notch激活通常指导组织构图，表明它可能会影响肿瘤的微环境。在这里，我们显示肿瘤细胞中的Notch调节两种强大的促炎细胞因子IL1β和CCL2的表达，以及肿瘤相关巨噬细胞（TAM）的募集。Notch还通过TAM调节TGFβ介导的肿瘤细胞活化，从而在这两种细胞类型之间闭合了Notch依赖性旁分泌信号传导环。我们使用小鼠模型，其中Notch可以在自发性乳腺癌中进行调节，以确认IL1β和CCL2的产生以及巨噬细胞募集是Notch依赖性的。在人类疾病中，表达阵列分析表明，Notch活化，IL1β和CCL2产生，巨噬细胞浸润和BLBC之间有着惊人的联系。

启示： BLBC具有攻击性，对有效靶向治疗的需求尚未得到满足。我们的数据突出显示了Notch激活的BLBC中的免疫治疗机会。有效的IL1β和CCL2拮抗剂目前正在临床上治疗良性炎性疾病，它们向癌症诊所的过渡可能会产生迅速的影响。巨蟹座Discov; 7（11）；1320–35。©2017 AACR。

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