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Targeting c-Jun Is a Potential Therapy for Luminal Breast Cancer Bone Metastasis
Yuxuan Han1, Shota Katayama1, Mitsuru Futakuchi2
1Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.
Abstract:
Luminal 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.
Implications:
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.
Insights
c-Jun protein promotes bone metastasis in luminal breast cancer by driving tumor cell migration and osteoclast activation. Targeting c-Jun may offer a new therapeutic strategy for preventing bone metastasis in this subtype.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metastasis
Background:
- Luminal breast cancer frequently metastasizes to bone, but mechanisms remain unclear due to limited models.
- Previous development of MCF7-derived bone metastatic cell lines (MCF7-BM) provides a platform for investigation.
Purpose of the Study:
- To characterize MCF7-BM cell lines and identify novel markers for luminal breast cancer bone metastasis.
- To elucidate the role of identified markers in the bone metastatic process and therapeutic potential.
Main Methods:
- Characterization of MCF7-BM cell lines.
- Assessment of c-Jun protein levels and functional impact on cell migration, transformation, and osteolytic activity.
- In vivo studies using dominant-negative c-Jun.
- Analysis of c-Jun expression in bone metastatic lesions.
- Investigation of c-Jun's role in the crosstalk between tumor cells and osteoclasts.
- Pharmacological inhibition of c-Jun using JNK-IN-8.
- Correlation of c-Jun downstream signals with patient prognosis.
Main Results:
- c-Jun protein is upregulated in MCF7-BM cells and promotes tumor cell migration, transformation, and osteolytic ability.
- Inhibition of c-Jun reduced bone metastatic lesions and frequency in vivo.
- c-Jun overexpression creates a vicious cycle with osteoclasts via enhanced calcium-induced migration and BMP5 release.
- JNK inhibitor JNK-IN-8 suppressed tumorigenesis and bone metastasis.
- c-Jun downstream signals correlate with clinical prognosis in luminal breast cancer patients.
Conclusions:
- c-Jun is a novel marker and key mediator of bone metastasis in luminal breast cancer.
- Targeting c-Jun or its signaling pathway presents a potential therapeutic strategy for preventing bone metastasis in this specific breast cancer subtype.
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