Notch Shapes the Innate Immunophenotype in Breast Cancer

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. 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. .

NOTCH and DNA repair pathways are more frequently targeted by genomic alterations in inflammatory than in non‐inflammatory breast cancers

“…We applied a 384‐gene signature of NOTCH activation (Villanueva et al , ) to expression data of the International IBC Consortium set. As expected (Shen et al , ), the activation score was higher in the TN samples than in the HR+/HER2− samples ( P = 2.41E‐50, one‐way ANOVA test Fig. B), validating its robustness.…”

NRSN2 promotes breast cancer metastasis by activating PI3K/AKT/mTOR and NF‑κB signaling pathways

“…The tumor volume of wild-type MDA-MB-231-injected mice at day 27 was ~2,100 mm 3 . The difference in the tumor volumes between the present study and the study by Shen et al (27) may be due to the types of mice used and the number of cells injected. The results from the present study demonstrated that NRSN2 stimulated PI3K/AKT/mTOR and NF-κB phosphorylation in MDA-MB-231 cells, which further promoted breast cancer cells growth both in vitro and in vivo.…”

“…Shen et al (27) reported that the tumor volume in 6-week-old female NOD/SCID mice injected with wild-type MDA-MB-231 cells (1x10 6 cells in 30 µl PBS) was ~200 mm 3 at day 22. In the present study, specific pathogen-free female Balb/c nude mice were injected with MDA-MB-231 cells transfected with pRK5-hNRSN2-or pRK5-vector (control; 1x10 7 cells) or MDA-MB-231 cells to analyze the role of NRSN2 in breast cancer growth.…”

Effect of miR‑449a‑mediated Notch signaling pathway on the proliferation, apoptosis and invasion of papillary thyroid carcinoma cells

“…The Notch signaling pathway as an important mechanism determining cell fate plays a vital role in the regulation of cell differentiation and development (21). The Notch signaling pathway also plays an important role in cell proliferation and apoptosis (24)(25)(26). Aberrantly high-expression of Notch receptor and its ligands in cancer cells has been confirmed in various cancers (27,28).…”