Abstract
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.This article is highlighted in the In This Issue feature, p. 1201.
Highlights
Breast cancer is the most common cancer in women worldwide and remains a leading cause of cancer death [1]
The current understanding is that Notch promotes tumorigenesis through cell-cycle deregulation, inhibition of apoptosis, and by reprogramming differentiation; tumor progression is facilitated by Notch through epithelial– mesenchymal transition and by regulating self-renewal of cancer stem cells [42]
We show that Notch designs the tumor microenvironment (TME) by regulating cytokine activities that control bidirectional signaling between tumor cells and tumor-associated macrophages (TAM)
Summary
Breast cancer is the most common cancer in women worldwide and remains a leading cause of cancer death [1]. It is a heterogeneous disease with multiple subtypes that display different patterns of gene expression, prognosis, and response to treatment [2]. Molecular targeted therapies have substantially improved survival in ER/PR-positive and HER2-amplified breast cancer, BLBC is without effective targeted treatment. This presents a significant clinical problem: BLBC is aggressive, with poor prognosis, and comprises 15% of all breast cancers, primarily affecting young women, people of African or Hispanic ancestry, and those with BRCA1 mutations.
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