Open AccessStress signaling in breast cancer cells induces matrix components that promote chemoresistant metastasis
Author(s) -
InsuaRodríguez Jacob,
Pein Maren,
Hongu Tsunaki,
Meier Jasmin,
Descot Arnaud,
Lowy Camille M,
De Braekeleer Etienne,
Sinn HansPeter,
Spaich Saskia,
Sütterlin Marc,
Schneeweiss Andreas,
Oskarsson Thordur
Publication year - 2018
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201809003
Subject(s) - metastasis , breast cancer , cancer research , signal transduction , cancer , medicine , biology , chemistry , microbiology and biotechnology
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 ( SPP 1), and tenascin C ( TNC ), that promote lung metastasis. We demonstrate that both SPP 1 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 SPP 1 or TNC expression sensitizes experimental mammary tumors and metastases to chemotherapy, thus providing insights to consider for future treatment strategies against metastatic breast cancer.