Breast cancer dissemination promoted by a neuregulin-collagenase 3 signalling node
S Seoane1, J C Montero1, A Ocaña2
1Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain.
Abstract:
Advances in the treatment of breast cancer have resulted in increased survival. However, in the metastatic setting, the disease remains incurable. Therefore, understanding of the mechanisms that promote dissemination of breast cancer cells may favor the development of novel therapeutic strategies to fight those tumors. Here, we show that the ErbB ligands, Neuregulins (NRGs), promote metastatic dissemination of breast cancer cells by switching on a kinase-metalloproteinase network. Clinicopathological analyses demonstrated that NRG expression in breast tumors associated to lymph node invasion and poor patient outcome. Preclinical in vivo analyses showed that NRG expression favored in situ tumor growth, local spreading and metastatic dissemination. Genomic, biochemical and functional studies identified matrix metalloproteinases, particularly stromelysin 2 and collagenase 3, as key mediators of the NRG-induced dissemination properties of breast cancer cells. Mechanistic analyses demonstrated that NRG augmented metalloproteinase expression through a route controlled by ERK1/2 kinases. ERK1/2 increased collagenase 3 expression by controlling the activity of an SBF1-related transcription factor. In conclusion, we describe a pathway linked to breast cancer dissemination. The clinical availability of agents that target some of the components of this signalling pathway suggests that patients with tumors fed by NRGs or other factors able to activate the ERK-Collagenase 3 route may benefit from agents that act on that signalling axis.
Insights
Neuregulins (NRGs) activate a network of kinases and metalloproteinases, promoting breast cancer metastasis. Targeting this NRG-activated pathway may offer new therapeutic strategies for incurable metastatic breast cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Breast cancer treatment advances have improved survival, but metastatic disease remains incurable.
- Understanding breast cancer cell dissemination mechanisms is crucial for developing novel therapies.
- Neuregulins (NRGs) are ErbB ligands implicated in various cellular processes.
Purpose of the Study:
- To investigate the role of Neuregulins (NRGs) in promoting breast cancer metastasis.
- To identify the molecular network mediating NRG-induced cancer cell dissemination.
- To explore potential therapeutic targets within the identified pathway.
Main Methods:
- Clinicopathological analysis of NRG expression in patient tumors.
- Preclinical in vivo studies assessing tumor growth and metastasis.
- Genomic, biochemical, and functional assays to identify key mediators.
- Mechanistic studies involving kinase and transcription factor activity analysis.
Main Results:
- NRG expression in breast tumors correlated with lymph node invasion and poor patient outcomes.
- In vivo studies showed NRG promotes tumor growth, local spread, and metastasis.
- Matrix metalloproteinases, specifically stromelysin 2 and collagenase 3, were identified as key mediators.
- NRG enhances metalloproteinase expression via ERK1/2 kinases and an SBF1-related transcription factor.
Conclusions:
- A novel pathway linking NRGs to breast cancer dissemination through a kinase-metalloproteinase network is described.
- ERK1/2 kinases and collagenase 3 are critical components of this NRG-induced metastatic pathway.
- Targeting components of this pathway, such as agents acting on the ERK-Collagenase 3 axis, may benefit patients with NRG-driven tumors.
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