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Legumain inhibitor prevents breast cancer bone metastasis by attenuating osteoclast differentiation and function

Junsong Chen1, Wenke Xu1, Kaiyuan Song1

  • 1Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China.

Bone
|January 26, 2023
PubMed

Insights

A novel compound, BIC-113, targeting Asparagine endopeptidase (AEP), effectively inhibits breast cancer bone metastasis and osteolytic lesions. Combined with epirubicin, it shows potential for treating metastatic breast cancer by reducing osteoclast formation and epithelial-mesenchymal transition.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Breast cancer metastasis to bone, particularly osteolytic lesions, significantly increases mortality in female patients.
  • Identifying novel therapeutic targets for osteolytic bone metastases is crucial for improving patient outcomes.
  • Asparagine endopeptidase (AEP) plays a role in cancer progression, making it a potential therapeutic target.

Purpose of the Study:

  • To investigate the efficacy of an AEP inhibitor, compound BIC-113, in combination with epirubicin for treating breast cancer bone metastasis.
  • To evaluate the effects of BIC-113 on osteoclast differentiation and Epithelial-Mesenchymal Transition (EMT) in a murine model.

Main Methods:

  • A murine model of breast cancer bone metastasis was established using 4T1.2 cells.
  • Animals were treated with compound BIC-113, epirubicin, or a combination thereof.
  • Bioluminescent imaging, X-rays, Western blotting, and transwell assays were used to assess metastasis, osteolytic lesions, gene expression, and cell invasion/migration.

Main Results:

  • Compound BIC-113 inhibited AEP activity, affecting cancer cell invasion and migration without impacting cell growth.
  • The combination of BIC-113 and epirubicin significantly inhibited breast cancer bone metastasis and attenuated osteolytic lesions.
  • Treatment suppressed osteoclast differentiation and reversed EMT, evidenced by increased E-cadherin expression.

Conclusions:

  • Compound BIC-113, as an AEP inhibitor, demonstrates potential in preventing breast cancer bone metastasis.
  • The combination therapy of BIC-113 and epirubicin offers a promising strategy for managing osteolytic bone metastases by targeting osteoclast formation and EMT.
  • This approach may improve therapeutic outcomes for patients with advanced breast cancer.
Keywords:
Asparagine endopeptidaseBone metastasisBreast cancerEpithelial-mesenchymal transitionOsteoclast

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