Stress signaling in breast cancer cells induces matrix components that promote chemoresistant metastasis.
EMBO Mol Med
; 10(10)2018 10.
Article
em En
| MEDLINE
| ID: mdl-30190333
ABSTRACT
Metastatic progression remains a major burden for cancer patients and is associated with eventual resistance to prevailing therapies such as chemotherapy. Here, we reveal how chemotherapy induces an extracellular matrix (ECM), wound healing, and stem cell network in cancer cells via the c-Jun N-terminal kinase (JNK) pathway, leading to reduced therapeutic efficacy. We find that elevated JNK activity in cancer cells is linked to poor clinical outcome in breast cancer patients and is critical for tumor initiation and metastasis in xenograft mouse models of breast cancer. We show that JNK signaling enhances expression of the ECM and stem cell niche components osteopontin, also called secreted phosphoprotein 1 (SPP1), and tenascin C (TNC), that promote lung metastasis. We demonstrate that both SPP1 and TNC are direct targets of the c-Jun transcription factor. Exposure to multiple chemotherapies further exploits this JNK-mediated axis to confer treatment resistance. Importantly, JNK inhibition or disruption of SPP1 or TNC expression sensitizes experimental mammary tumors and metastases to chemotherapy, thus providing insights to consider for future treatment strategies against metastatic breast cancer.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Mama
/
Transdução de Sinais
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Resistencia a Medicamentos Antineoplásicos
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Metástase Neoplásica
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article