Open Access

REVIEW

Research Progress on Signaling Pathways in Breast Cancer Bone Metastasis

Yunhong Li^1,2,#, Tianqi Li^3,#, Fenglian Liang^4,#, Lu Kuang⁴, Yizhi Li^5,6, Hongsheng Li^1,*

1 Department of Breast Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, 78 Hengzhigang Rd, Guangzhou, China
2 Southern Medical University Hospital of Integrated Traditional Chinese and Western Medicine, Southern Medical University, Guangzhou, China
3 The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
4 The Affiliated Guangzhou Twelfth People’s Hospital, Guangzhou Medical University, Guangzhou, China
5 The Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
6 Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

* Corresponding Author: Hongsheng Li. Email:
# These authors contributed equally to this work

(This article belongs to the Special Issue: Cancer Metastasis)

Oncology Research 2026, 34(10), 14 https://doi.org/10.32604/or.2026.079898

Received 30 January 2026; Accepted 24 August 2026; Issue published 14 September 2026

Abstract

Breast cancer (BC) has become the most commonly diagnosed malignant tumor among women worldwide, with approximately 70% of patients with advanced BC developing bone metastases. These metastases trigger bone destruction and skeletal-related events (SREs) and significantly reduce patient survival. In recent years, research into the mechanisms underlying BC bone metastasis has advanced rapidly. Molecular biological and genomic studies have revealed that BC bone metastasis is co-regulated by multiple signaling pathways through crosstalk between BC cells and the bone microenvironment. This review analyzes the research progress of signaling pathways involved in BC bone metastasis and systematically elaborates four core cascades: Wingless-related integration site (Wnt)/β-catenin, transforming growth factor-β (TGF-β), RANK/receptor activator of nuclear factor-κB ligand (RANKL)/osteoclastogenesis inhibitory factor (OPG), and phosphatidylinositol 3-Kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR). It explains how each pathway mediates epithelial-mesenchymal transition (EMT), excessive Osteoclast (OC) activation, maintenance of cancer stem cell stemness, and the formation of an immunosuppressive microenvironment. The positive feedback loops and reciprocal crosstalk between these pathways are also summarized, which together fuel the vicious cycle of osteolytic bone metastasis. This paper further consolidates therapeutic strategies targeting the aforementioned signaling pathways and outlines cutting-edge therapeutic approaches and emerging research hotspots. Nevertheless, critical obstacles including complex pathway compensation, drug resistance, and dysregulated bone immunity remain major bottlenecks hindering clinical translation. Future research will leverage single-cell sequencing and multi-omics technologies to identify pivotal molecular targets and develop potent combinatorial therapies. Such advances will facilitate the implementation of precise, individualized treatment for BC bone metastasis and ultimately improve the quality of life and long-term clinical outcomes of patients with advanced bone-metastatic disease.

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