Yuxuan Han, Shota Katayama, Mitsuru Futakuchi, Kazuya Nakamichi, Yutaro Wakabayashi, Mai Sakamoto, Jun Nakayama, Kentaro Semba
Molecular cancer research : MCR 2023 Sep 01Luminal breast cancer has the highest bone metastasis frequency among all breast cancer subtypes; however, its metastatic mechanism has not been elucidated because of a lack of appropriate models. We have previously developed useful bone metastatic cell lines of luminal breast cancer using MCF7 cells. In this study, we characterized bone metastatic MCF7-BM cell lines and identified c-Jun as a novel bone metastasis marker of luminal breast cancer. The protein level of c-Jun was upregulated in MCF7-BM cells compared with that in parental cells, and its deficiency resulted in the suppression of tumor cell migration, transformation, and reduced osteolytic ability. In vivo, dominant-negative c-Jun exhibited smaller bone metastatic lesions and a lower metastatic frequency. Histologic analysis revealed that c-Jun expression was heterogeneous in bone metastatic lesions, whereas c-Jun overexpression mediated a vicious cycle between MCF7-BM cells and osteoclasts by enhancing calcium-induced migration and releasing the osteoclast activator BMP5. Pharmacological inhibition of c-Jun by the Jun amino-terminal kinase (JNK) inhibitor JNK-IN-8 effectively suppressed tumorigenesis and bone metastasis in MCF7-BM cells. Furthermore, c-Jun downstream signals were specifically correlated with the clinical prognosis of patients with the luminal subtype of breast cancer. Our results illustrate the potential benefits of a therapy that targets c-Jun to prevent bone metastasis in luminal breast cancer. c-Jun expression mediates bone metastasis in luminal breast cancer by forming a vicious cycle in the bone microenvironment, which reveals potential strategies for subtype-specific bone metastasis therapy. ©2023 American Association for Cancer Research.
Yuxuan Han, Shota Katayama, Mitsuru Futakuchi, Kazuya Nakamichi, Yutaro Wakabayashi, Mai Sakamoto, Jun Nakayama, Kentaro Semba. Targeting c-Jun Is a Potential Therapy for Luminal Breast Cancer Bone Metastasis. Molecular cancer research : MCR. 2023 Sep 01;21(9):908-921
PMID: 37310848
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