Breast Cancer with Bone Metastasis: Molecular Insights and Clinical Management

Abstract

Despite the remarkable advances in the diagnosis and treatment of breast cancer patients, the presence or development of metastasis remains an incurable condition. Bone is one of the most frequent sites of distant dissemination and negatively impacts on patient's survival and overall frailty. The interplay between tumor cells and the bone microenvironment induces bone destruction and tumor progression. To date, the clinical management of bone metastatic breast cancer encompasses anti-tumor systemic therapies along with bone-targeting agents, aimed at slowing bone resorption to reduce the risk of skeletal-related events. However, their effect on patients' survival remains controversial. Unraveling the biology that governs the interplay between breast neoplastic cells and bone tissue would provide means for the development of new therapeutic agents. This article outlines the state-of-the art in the characterization and targeting the bone metastasis in breast cancer, focusing on the major clinical and translational studies on this clinically relevant topic.

Keywords: bone metastasis; bone-targeting therapy; breast cancer; therapy resistance; tumor progression; tumor-bone microenvironment.

Figure 1

Schematic representation of the processes involved in breast cancer bone metastasis formation. Metastatic tumor cells migrate from the breast primary site to the bone through the bloodstream. Once they arrive in the target part of the skeleton, these neoplastic clones are able to activate a cascade of events that lead to a biological vicious cycle, ultimately leading to the dysregulation of the normal bone homeostasis. In particular, breast cancer bone metastasis can be either osteolytic or osteoblastic based on the type of mechanism that prevails in the bone disequilibrium (i.e., bone resorption or formation). When osteoclastogenic pathways are activated by the metastatic clones, several trophic factors, cytokines, and chemokines (e.g., PTHrP, IL1, IL6, IL11, PGE2, TNF and M-CSF) are secreted. These, either directly or indirectly (via osteoblasts), stimulate osteoclast differentiation and activity through a vicious cycle. Moreover, RANKL produced by both breast cancer cells and osteoblasts binds on RANK receptors, further stimulating the differentiation of the osteoclasts. These events lead to enhanced bone resorption and consequent release of metalloproteases, HCl and matrix-embedded growth factors (e.g., IGF-1, TGF-β, FGF and PDGF), which in turn cause breakdown of the collagenous matrix and promote cancer cell proliferation and tumor progression, respectively. In osteoblastic lesions, ET1 secreted by breast cancer cells inhibits the expression of DKK-1, which normally blocks Wnt signaling decreasing osteoblastic differentiation. Inhibition of DKK-1 results in an increased osteoblast activity favoring uncontrolled bone formation. Abbreviations: PTHrP, parathyroid hormone-related peptide; IL1, interleukin 1; IL6, interleukin 6; IL11, interleukin 11; PGE2, prostaglandin E2; TNF, tumor necrosis factor; M-CSF, macrophage colony-stimulating factor; HCl, hydrochloric acid; IGF1, insulin-growth factor 1; TGFβ, transforming growth factor β; FGF, fibroblast growth factor; PDGF, platelet-derived growth factor. ET1, endothelin 1; DKK1, Dickkopf 1.