Exosomal miR-19a and IBSP cooperate to induce osteolytic bone metastasis of estrogen receptor-positive breast cancer
Kerui Wu, Jiamei Feng, Feng Lyu, Fei Xing, Sambad Sharma, Yin Liu, Shih-Ying Wu, Dan Zhao, Abhishek Tyagi, Ravindra Pramod Deshpande, Xinhong Pei, Marco Gabril Ruiz, Hiroyuki Takahashi, Shunsuke Tsuzuki, Takahiro Kimura, Yin‐Yuan Mo, Yusuke Shiozawa, Ravi Singh, Kounosuke Watabe
Abstract
Abstract Bone metastasis is an incurable complication of breast cancer. In advanced stages, patients with estrogen-positive tumors experience a significantly higher incidence of bone metastasis (>87%) compared to estrogen-negative patients (<56%). To understand the mechanism of this bone-tropism of ER + tumor, and to identify liquid biopsy biomarkers for patients with high risk of bone metastasis, the secreted extracellular vesicles and cytokines from bone-tropic breast cancer cells are examined in this study. Both exosomal miR-19a and Integrin-Binding Sialoprotein (IBSP) are found to be significantly upregulated and secreted from bone-tropic ER + breast cancer cells, increasing their levels in the circulation of patients. IBSP is found to attract osteoclast cells and create an osteoclast-enriched environment in the bone, assisting the delivery of exosomal miR-19a to osteoclast to induce osteoclastogenesis. Our findings reveal a mechanism by which ER + breast cancer cells create a microenvironment favorable for colonization in the bone. These two secreted factors can also serve as effective biomarkers for ER + breast cancer to predict their risks of bone metastasis. Furthermore, our screening of a natural compound library identifies chlorogenic acid as a potent inhibitor for IBSP-receptor binding to suppress bone metastasis of ER + tumor, suggesting its preventive use for bone recurrence in ER + patients.