Dataset Information

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.

SUBMITTER: Wu K

PROVIDER: S-EPMC8408156 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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

Wu Kerui K Feng Jiamei J Lyu Feng F Xing Fei F Sharma Sambad S Liu Yin Y Wu Shih-Ying SY Zhao Dan D Tyagi Abhishek A Deshpande Ravindra Pramod RP Pei Xinhong X Ruiz Marco Gabril MG Takahashi Hiroyuki H Tsuzuki Shunsuke S Kimura Takahiro T Mo Yin-Yuan YY Shiozawa Yusuke Y Singh Ravi R Watabe Kounosuke K

Nature communications 20210831 1

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<sup>+</sup> 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 examine ...[more]

PMID: 34465793

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Project description:RAS activation is a key determinant of breast cancer progression and metastasis. However, the role of the interaction among exosomes, RAS and microRNAs (miRNAs/miRs) in the osteolytic bone metastasis of breast cancer remains unclear. Therefore, the present study aimed to examine the role of activated RAS (KRAS, HRAS and NRAS) in the release of exosome‑mediated osteoclastogenic miRNAs and to elucidate their functional role in bone microenvironment remodeling in vitro and in vivo. Exosomes derived from RAS‑activated breast cancer cells promoted RANKL‑induced osteoclastogenesis; however, RAS inhibition abolished this effect. miR‑494‑3p, miR‑4508 and miR‑6869‑5p were identified as osteoclastogenic miRNAs in the exosomes secreted by RAS‑activated breast cancer cells. The levels of these osteoclastogenic miRNAs in the sera of patients with human epidermal growth factor receptor 2‑positive luminal breast cancer were significantly higher than those in the sera of patients with triple‑negative breast cancer. miR‑494‑3p exhibited both osteoclastogenic and anti‑osteoblastogenic activity. Treatment with a miR‑494‑3p inhibitor abolished the exosome‑mediated increase in RANKL‑induced osteoclastogenesis. Treatment with a miR‑494‑3p mimic enhanced RANKL‑induced osteoclast formation; however, treatment with its inhibitor suppressed this effect by targeting leucine‑rich repeat‑containing G‑protein coupled receptor 4 in osteoclast precursors. Furthermore, miR‑494‑3p inhibited bone morphogenetic protein 2‑induced osteoblast formation by targeting semaphorin 3A. In a mouse model, exosomes derived from breast cancer cells promoted osteolytic bone lesions; however, treatment with a miR‑494‑3p inhibitor significantly suppressed this effect. On the whole, the present study provides a novel mechanism, demonstrating that the RAS activation of breast cancer cells induces osteolytic bone metastasis by stimulating the exosome‑mediated transfer of osteoclastogenic miRNAs, including miR‑494‑3p to bone cells.

Dataset Information

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

Publications

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

Similar Datasets

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