Bone Metastasis in Estrogen Receptor-Positive Breast Cancer: Molecular Insights and Therapeutic Advances

TL;DR

This paper reviews the molecular mechanisms behind bone metastasis in estrogen receptor-positive breast cancer and recent advances in treatment strategies.

Contribution

The paper provides a systematic summary of tumor-bone microenvironment interactions and novel therapeutic approaches for ER+ breast cancer bone metastasis.

Findings

ER+ breast cancer metastasizes to bone due to complex tumor-bone microenvironment interactions.

Dysregulated pathways like PI3K/AKT/mTOR and TGF-β contribute to bone metastasis progression.

New therapies include next-generation endocrine treatments and bone-targeted agents.

Abstract

Estrogen receptor-positive (ER+) breast cancer represents the most prevalent molecular subtype of breast cancer, characterized by hormone-dependent growth, relatively indolent progression, and a pronounced tendency to metastasize to bone. While endocrine therapies remain the cornerstone of treatment, a significant proportion of ER+ tumors eventually develop resistance, culminating in distant metastases—most frequently to the bone. Bone metastasis substantially compromises patient survival and quality of life, highlighting the critical need to elucidate its molecular underpinnings. Recent multi-omics and mechanistic studies have shed light on the complex interplay between tumor-intrinsic signaling pathways, such as dysregulated ER signaling, PI3K/AKT/mTOR, TGF-β, and Hippo pathways, and the bone microenvironment, including osteoclast activation, immune suppression, and stromal remodeling. This review systematically summarizes the current understanding of the molecular mechanisms driving bone metastasis in ER+ breast cancer, with a particular focus on tumor–bone microenvironment crosstalk and key regulatory pathways. Additionally, we discuss recent advances in therapeutic strategies, encompassing next-generation endocrine therapies, CDK4/6 inhibitors, bone-targeted agents, and pathway-specific inhibitors. Together, these insights pave the way for more effective and personalized interventions against ER+ breast cancer with bone involvement.

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