Exosomal miR-19a and IBSP cooperate to induce osteolytic bone metastasis of estrogen receptor-positive breast cancer.
Kerui WuJiamei FengFeng LyuFei XingSambad SharmaYin LiuShih-Ying WuDan ZhaoAbhishek TyagiRavindra Pramod DeshpandeXinhong PeiMarco Gabril RuizHiroyuki TakahashiShunsuke TsuzukiTakahiro KimuraYin-Yuan MoYusuke ShiozawaRavi SinghKounosuke WatabePublished in: Nature communications (2021)
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.
Keyphrases
- bone mineral density
- estrogen receptor
- bone loss
- breast cancer cells
- soft tissue
- end stage renal disease
- bone regeneration
- chronic kidney disease
- postmenopausal women
- long non coding rna
- ejection fraction
- newly diagnosed
- cell proliferation
- peritoneal dialysis
- prognostic factors
- cell death
- risk factors
- dna methylation
- signaling pathway
- risk assessment
- induced apoptosis
- patient reported outcomes
- endoplasmic reticulum stress
- ionic liquid
- climate change
- pi k akt
- human health