Exosomal miR-19a and IBSP cooperate to induce osteolytic bone metastasis of estrogen receptor-positive breast cancer

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.

MicroRNAs: Emerging Regulators of Metastatic Bone Disease in Breast Cancer

“…Guo and colleagues showed that breast-cancercell-derived exosomes containing miR-20a-5p stimulated the proliferation of bone marrow macrophages and differentiation into osteoclasts in vitro [66]. Recently, Wu et al reported that exosomal miR-19a not only is a factor secreted by ER+ bone metastatic breast cancer cells, but also mediates osteolysis by creating an osteoclast-enriched environment within the bone in the presence of integrin-binding sialoprotein [72].…”

The Emerging Role of MicroRNAs in Bone Diseases and Their Therapeutic Potential

“…Yuan et al [ 126 ] revealed that exosomal translocation of miR-21 from breast cancer cells to osteoclasts promoted the establishment of a pre-metastatic niche by modulating the protein levels of programmed cell death 4 (PDCD4). A recent study published in 2021 described that the exosomal transport of miR-19a and integrin-binding sialoprotein (IBSP) might trigger the molecular mechanism of metastasis in osteoclasts and estrogen receptor-positive (ER + ) breast cancer and induce the activation of the vicious cycle [ 127 ].…”

Roles of the Exosomes Derived From Myeloid-Derived Suppressor Cells in Tumor Immunity and Cancer Progression

“…Exosomes exert cancer-inhibiting or cancer-promoting effects. For example, exosomal miR-19a is delivered to osteoblasts to promote bone metastasis in breast cancer (9). While human umbilical cord mesenchymal stem cell -derived exosomal miR-320a inhibits lung cancer cell growth via SOX4/Wnt/b-catenin axis (10).…”