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

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. Histological 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.

Beyond boundaries: unraveling innovative approaches to combat bone-metastatic cancers

“…A study found that the protein c-Jun levels increased in MCF7-BM cells compared to the original cells ( 162 ). Additionally, the absence of c-Jun was observed to suppress tumor cell migration, transformation, and the ability to cause bone destruction (osteolysis).…”

“…These insights open up promising avenues for the development of subtype-specific therapies that can effectively tackle bone metastasis in luminal breast cancer. By targeting c-Jun, researchers and clinicians may have the opportunity to provide more tailored and effective treatments for patients with this particular subtype of breast cancer, ultimately leading to improved outcomes and better quality of life ( 162 ).…”