Stromal NRG1 in luminal breast cancer defines pro-fibrotic and migratory cancer-associated fibroblasts

HER3 is highly expressed in luminal breast cancer subtypes. Its activation by NRG1 promotes activation of AKT and ERK1/2, contributing to tumour progression and therapy resistance. HER3-targeting agents that block this activation, are currently under phase 1/2 clinical studies, and although they hav...

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Bibliographic Details
Published in:Oncogene 2021-04, Vol.40 (15), p.2651-2666
Main Authors: Berdiel-Acer, Mireia, Maia, Ana, Hristova, Zhivka, Borgoni, Simone, Vetter, Martina, Burmester, Sara, Becki, Corinna, Michels, Birgitta, Abnaof, Khalid, Binenbaum, Ilona, Bethmann, Daniel, Chatziioannou, Aristotelis, Hasmann, Max, Thomssen, Christoph, Espinet, Elisa, Wiemann, Stefan
Format: Article
Language:English
Subjects:
13/1
13/95
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631/337/475
631/67/1347
631/67/327
692/53/2422
96/106
AKT protein
Apoptosis
Breast cancer
Breast Neoplasms - genetics
Cancer
Cancer-Associated Fibroblasts - metabolism
Cell Biology
Cell migration
Development and progression
Epidermal growth factor
Female
Fibroblasts
Gene expression
Genetic aspects
Health aspects
Human Genetics
Humans
Hyaluronan synthase
Hyaluronic acid
Internal Medicine
Medicine
Medicine & Public Health
Neuregulin-1 - metabolism
Oncology
Oncology, Experimental
Paracrine signalling
Phenotypes
Phosphorylation
Proteomics - methods
Tumor Microenvironment
Tumors
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Summary:HER3 is highly expressed in luminal breast cancer subtypes. Its activation by NRG1 promotes activation of AKT and ERK1/2, contributing to tumour progression and therapy resistance. HER3-targeting agents that block this activation, are currently under phase 1/2 clinical studies, and although they have shown favorable tolerability, their activity as a single agent has proven to be limited. Here we show that phosphorylation and activation of HER3 in luminal breast cancer cells occurs in a paracrine manner and is mediated by NRG1 expressed by cancer-associated fibroblasts (CAFs). Moreover, we uncover a HER3-independent NRG1 signaling in CAFs that results in the induction of a strong migratory and pro-fibrotic phenotype, describing a subtype of CAFs with elevated expression of NRG1 and an associated transcriptomic profile that determines their functional properties. Finally, we identified Hyaluronan Synthase 2 (HAS2) , a targetable molecule strongly correlated with NRG1 , as an attractive player supporting NRG1 signaling in CAFs.
ISSN:0950-9232
1476-5594
DOI:10.1038/s41388-021-01719-3