Targeting c-Jun Is a Potential Therapy for Luminal Breast Cancer Bone Metastasis
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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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