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. 2023 Jul 3;96(1150):20230117. doi: 10.1259/bjr.20230117

Advances in the study of biomarkers related to bone metastasis in breast cancer

Dongcheng Xu 1,2,1,2, Mingxing Tang 1,2,1,2,✉
PMCID: PMC10546430  PMID: 37393528

Abstract

Breast cancer is by far the most common malignancy in females. And bone is the most common site of distant metastasis in breast cancer, accounting for about 65 to 75% of all metastatic breast cancer patients. 1,2 Bone metastasis is an important factor affecting the prognosis of breast cancer. When patients have early-stage breast cancer without metastasis, their 5-year survival rate is as high as 90%, and once metastasis occurs, their 5-year survival rate will drop to 10%. 3 Bone radionuclide imaging (ECT), X-ray, CT scan, MRI and other imaging tests to diagnose breast cancer bone metastasis are commonly used in clinical, It is currently believed that breast cancer bone metastasis is a multistep process: first, breast cancer cells need to acquire invasive and metastatic properties; breast cancer cells enter the blood circulation and migrate from blood breast cancer cells enter the blood circulation and migrate from blood vessels to bone tissue in a targeted manner; breast cancer cells adhere and remain in bone tissue and colonise it; and finally, it leads to bone destruction. 4 Several key molecules are involved in breast cancer bone metastasis, and serum biomarkers are generally able to detect pathological changes earlier Several key molecules are involved in breast cancer bone metastasis, and serum biomarkers are generally able to detect pathological changes earlier than imaging. 5 This review describes the progress of serum biomarkers for breast cancer bone metastasis.

Tissue markers for breast cancer

Integrin beta-like 1 (ITGBL1) is a protein homologous to the integrin β subunit sequence. 1–5 In clinical cases, in vivo animal experiments and in vitro cytology, high expression of ITGBL1 promotes the expression of genes associated with bone matrix remodelling in breast cancer cells to form an osteomimicry phenotype, which in turn nests, colonises and proliferates in the bone microenvironment and promotes osteoclast differentiation to form osteolytic bone metastases. 6 Breast cancer tissue experiments have shown that dedicator of cytokinesis protein 4 (DOCK4), nuclear p21-activated kinase 4 (PAK4), peroxiredoxin-4, (PRDX4), L-plastin (LPC1), macrophage-capping protein (CapG), GIPC interacting protein C terminus 1 (GIPC1) and other proteins were associated with the high expression of breast cancer bone metastasis. The high expression of these proteins is associated with breast cancer bone metastasis, suggesting that these proteins may be a potential marker of breast cancer bone metastasis. 7

Patients with positive hormone receptors (ER, PR), high expression of human epidermal growth factor receptor 2 (HER-2) and high Ki-67 expression in breast cancer tissues have a relatively high incidence of bone metastases. 8

Circulating tumour cells

Circulating tumour cells (CTCs) are mainly tumour cells in the human peripheral blood. One of the first clinical applications of CTC testing was as a prognostic indicator for breast cancer. 9 De Giorgi U et al found that the number of CTCs was significantly higher in breast cancer with bone metastases compared to breast cancer without bone metastases and correlated with severity. The number of CTCs in the blood also predicted survival in breast cancer. There was a correlation between CTC results and the FDG-PET/CT technique commonly used in clinical practice for bone metastases. 10 These results suggest that CTC may be a predictor and an aid to the diagnosis of bone metastases in breast cancer. It was also found that CTCs have different types such as epithelial, mesenchymal, and epithelial-mesenchymal cell types, and that different types of CTCs have different migratory and invasive abilities. 11,12 In the presence of CTC clusters of two or more tumour cells in the blood, blood CTC clusters are more likely to cause breast cancer metastasis than single CTCs. 13

Circulating cell-free nucleic acids

Circulating cell-free nucleic acids (cfNAs) are nucleic acids that are present in human body fluids in the extracellular free nucleic acid state, including circulating DNA and circulating RNA.

Circulating tumour DNA

Circulating cell-free DNA (cfDNA) is a hot topic of research. 14,15 cfDNA is derived from primary tumour cells, CTCs, micrometastases, as well as normal blood cells and stromal cells. 16 The amount of cfDNA in patients is positively correlated with tumour load. Madhavan et al found that plasma DII was significantly lower in breast cancer patients than in healthy subjects, and that DII can be used in the prognostic evaluation of metastatic breast cancer. 17 Circulating tumour DNA (ctDNA) is derived from the genome of tumour cells and carries tumour-specific mutations. It has the same biological properties as the original tumour tissue and is important for detecting metastasis and prognosis. 18 Mutations in the KRAS, BRCA1/2 and PIK3CA genes, which reflect the malignancy and prognosis of breast cancer, were originally detected using tissue specimens, but nowadays liquid biopsies can be performed on plasma specimens. 19 cfDNA can be used for DNA methylation detection, and 21 DNA hypermethylation hotspots significantly associated with metastatic breast cancer were detected using plasma specimens by whole-genome sodium sulfite sequencing byChristophe Legendre et al 20

Circulating RNA

MicroRNAs (miRNAs) are a class of non-coding single-stranded RNA molecules. miRNAs may also be markers of bone metastasis in breast cancer. Cellular and mouse experiments have shown that the miRNA-30 family inhibits bone metastasis in breast cancer through the regulation of multiple signaling pathways. 21 The TCGA database has been used to identify miR-19a, miR-93 and miR-106a from a wide range of miRNAs to predict breast cancer bone metastasis, and has been clinically validated. 22 A very large number of miRNAs were found to be involved in breast cancer bone metastasis (Table 1), and they are all potential biomarkers for breast cancer bone metastasis. 23

Table 1.

miRNAs involved in bone metastasis in breast cancer

Types of miRNAs miRNAs
Promoting bone metastases from breast cancer miR-10b, miR-19a, miR-20a-5p, miR-30s, miR-218
Inhibition of bone metastases from breast cancer miR-30a-b-c-d-e, miR-30s, miR-33a, miR-34a, miR-34a-5p, miR-124, miR-133a, miR-135, miR-141, miR-143, miR-190, miR-192, miR-203, miR-204, miR- 205, miR-211, miR-219, miR-379, miR-429, miR-1976
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Other RNAs are also involved in the regulation of breast cancer bone metastasis. Xu et al identified a new circular RNA, circIKBKB, which plays an important role in inducing the formation of a pre-stable ecological niche in bone by maintaining NF-κ b/bone remodeling factor signaling, leading to breast cancer bone metastasis. 24 Long-stranded non-coding RNAs (lncRNAs) such as MCM3AP-AS1 25 and MALAT1 26 are also involved in breast cancer bone metastasis.

Exosomes are microscopic vesicles between 30 and 200 nm in size, which are secreted by living cells and contain DNA, RNA, proteins and lipids. They are secreted by almost all types of cells and are found in a wide variety of body fluids such as serum, plasma and urine. Recent studies have found that exosomes (especially the various non-coding RNAs in them) play an important regulatory role in breast cancer bone metastasis. 27,28

Bone-directed migration markers for breast cancer cells

CTCs colonise the endosteal niche with the assistance of adhesion proteins and integrins. Bone is a suitable organ for CTC colonisation, which is determined by both the properties of the breast cancer cells themselves and the bone microenvironment in which they colonise. 29 The C-X-C motif chemokine ligand (CXCL) is a subtype that includes CXCL1 to CXCL16. CXCL12 is a member of the CXC subfamily of chemokines. CXCL12 is a member of the CXC subfamily. C-X-C motif chemokine receptor-4 (CXCR4) is a member of the CXC subfamily of chemokines, a group of seven transmembrane GPCRs that mediate the function of chemokines. It is a CXCL12-specific receptor. CXCL12 binds to acetyl heparan sulfate in the stromal cell membrane via a set of basic amino acids, exposing its terminal amino signalling region, and binds to its receptor CXCR4, which exerts its biological effects via the CXCL12/CXCR4 signalling pathway to induce cell migration. 30 CXCR4/CXCL12 is closely associated with bone metastasis in breast cancer. CXCR4 is highly expressed in breast cancer tissues and its expression level correlates with the extent of the lesion. In contrast, CXCL12 is highly expressed in organs where breast cancer commonly metastasises (e.g., bone marrow, lymph nodes, lung and liver). 31 CXCR4 has a high affinity for CXCL12, leading to the exit of breast cancer cells from blood vessels in the circulatory system and their colonisation in bone. In studies of normal breast tissue, breast cancer without bone metastases and breast cancer with bone metastases, CXCR4 expression was found to be elevated in breast cancer tissue and higher in breast tissue from patients with breast cancer with bone metastases, making it a possible new marker for breast cancer with bone metastases. 32 Other chemokines CXCL-5, CXCL-8, CXCL-10, CXCL-13, CX3CL-1, CCL-2, CXCR-6/CXCL-16,and CXCR-3/CXCL-10 also have similar effects. CXCR-6/CXCL-16 and CXCR-3/CXCL-10 have similar effects. 33

Interleukin-1β (IL-1β) may be another marker for the induction of tumour cell outgrowth. 29 IL-1β expression in primary tumours has been identified as a potential biomarker for predicting increased risk of bone metastases in breast cancer patients. Serum IL-1β levels in breast cancer patients are significantly higher in patients with bone metastases and correlate with severity. 34 The sensitivity and specificity of serum IL-1β for the diagnosis of bone metastases were 82 and 85%, respectively. 35,36 IL-1β is mainly responsible for the epithelial-mesenchymal transition (EMT) of tumour cells and can have an accelerating effect on the dissemination of tumour cells in the circulatory system. Once tumour cells reach bone tissue, IL-1β induces the expression of vascular cell adhesion molecules ICAM-1, VCAM-1 and E-selectin, promoting tumour cell colonisation in bone tissue. 29

Dispersal of tumour cells

Disseminated tumour cells (DTC) are CTCs that migrate and settle from blood vessels to distant organs. Although bone is a suitable organ for CTC colonisation, it is not very efficient. Studies have shown that DTC can be detected in bone in only 24% of CTC patients. 37,38 Tumour cells may grow only if DTC are in the bone remodelling compartment (BRC), otherwise they are dormant. It was found that only a small proportion of DCTs expressed the proliferation marker Ki-67, suggesting that the vast majority of tumour cells are dormant in the bone endoskeleton. 39

As bone is a common colonisation organ for breast cancer after blood dissemination, DTC is mainly detected using bone marrow specimens. DCT is a rare cell in bone marrow, with only one DTC in 106 ˜107 bone marrow cells. Cellular markers for DTC are similar to CTC and can be enriched and identified by cytokeratin (CK), epithelial cell adhesion molecule (EpCAM). 39 DTC in bone marrow DTC can be single or in clusters and are heterogeneous. Braun et al followed 4703 patients with operable breast cancer for 10 years to assess the impact of the bone marrow microenvironment on patients with breast cancer. The study showed that detection of DTC in the bone marrow was an independent predictor of early disease recurrence and death. 40 Cellular immunoassay of DTC can determine whether it is dormant. Nuclear Receptor Subfamily 2 Group F Member 1 (NR2F1) was found to be a marker of DTC dormancy. 41 Elevated expression of p27 induced Differentiated Embryonic Chondrocyte Gene 2 (DEC2) was also found in DTC dormant cells. 42 The presence of ALDH and CD44 expression in DTC and the lack of CD24 expression suggest that tumour stem cells are also present in DTC. Increased expression of TWIST1, SNAIL1 and LAMB1 was found in DTC, suggesting the presence of epithelial-mesenchymal transition (EMT) 39. The genomic information of bone marrow DTC was found to differ from that of in situ breast cancer cells and CTCs, and DTC single-cell sequencing is expected to be a new marker for breast cancer bone metastasis. 43

Markers of tumour cell activation and proliferation

When breast cancer cells develop bone metastases, they release a number of cytokines (e.g., interleukin 6, interleukin 11, parathyroid hormone-related protein, etc.), which in turn stimulate the synthesis of nuclear factor-κB activator ligand (RANKL) by osteoblasts, which binds to the NF-κB receptor activator (RANK) on the surface of osteoclasts to induce osteoclast differentiation and maturation, thereby initiating bone resorption. Resorption. Osteoprotegerin (OPG) is an inducible receptor for RANKL and binds to RANKL to reduce osteoclast production. In addition, the release of repair-promoting growth factors from the bone matrix (e.g., transforming growth factor β) positively feeds back to promote tumour cell growth. 44,45 Thus, the RANKL-RANK-OPG signalling pathway and related factors are key to the activation and proliferation of breast cancer cells in bone tissue, and they may all be biomarkers for the development of bone metastases from breast cancer (Table 2). 46

Table 2.

Markers of tumour cell activation and proliferation in bone tissue

Activation of proliferation markers Role Effect
Nuclear factor-κB activator ligand (RANKL) Binds to the RANK receptor on the surface of osteoclast precursors Osteoclast activation
Receptor activator of nuclear factor-κB (RANK) Binds specifically to RANKL Osteoclast activation
Osteoprotegerin (OPG) Inducible receptors for RANKL Reduces osteoclast production by binding to RANKL
Parathyroid hormone-related protein (PTHrP) Interacts with PTHR1 and promotes RANKL expression Promotes osteoclast-mediated bone resorption
Transforming growth factor β (TGF-β) Up-regulation of PTHrP expression Promotes osteoclast-mediated bone resorption
Insulin-like growth factor 1 (IGF-1) Promotes chemotaxis and colonisation of tumour cells Tumour cells proliferate in bone tissue
Interleukin-6 (IL-6) Induces osteoclastic action and inhibits osteogenesis Increased bone resorption and reduced bone formation
Interleukin-11 (IL-11) Induces osteoclastic action and inhibits osteogenesis Increased bone resorption and reduced bone formation
Prostaglandin E2 Increased RANKL expression Increased bone resorption
Macrophage colony-stimulating factor (M-CSF) Induces osteoclastic action and inhibits osteogenesis Increased bone resorption
Tumour necrosis factor α (TNF-α) Induces osteoclastic action and inhibits osteogenesis Increased bone resorption
Integrin (integrin) Promoting tumour cell colonisation of bone tissue Facilitates proliferation of tumour cells in bone tissue
E-calcified adhesion protein (E-cadherin) Intercellular adhesion Associated with infiltration and metastasis of tumour cells
Osteoblastin (OPN) Regulation of osteoblasts Regulation of bone resorption
Bone Salivary Protein (BSP) Regulation of osteoblasts Regulation of bone resorption
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Parathyroid hormone-related proteins

Parathyroid hormone-related protein (PTHrP) is a PTH-related peptide growth factor. Its synthesis is not regulated by serum calcium and circulating levels of PTHrP are very low in healthy adults. Serum PTHrP is elevated during lactation. PTHrP secreted by breast cancer cells can promote the development of breast cancer bone metastases by inducing RANKL secretion by osteoblasts, inhibiting OPG expression, regulating the RANKL-RANK-OPG signalling pathway, increasing osteoclast bone resorption activity, and promoting osteolytic bone resorption destruction. 47 Plasma PTHrP levels were found to be low in healthy adults, elevated in 2/3 of primary breast cancers and 90% of patients with bone metastases, and significantly elevated in patients with hypercalcaemic breast cancer with metastatic bone disease. 48 PTHrP is largely unexpressed in mastocytosis and significantly less expressed in breast cancer without bone metastases than in primary with bone metastases. This suggests that PTHrP may be involved in the malignant transformation of breast cancer and is associated with bone metastases in breast cancer.

Nuclear factor-κB receptor-activating factor ligands

The receptor activator of nuclear factor-κB ligand (RANKL) is mainly produced by osteoblasts and bone marrow stromal cells (e.g., fibroblasts, T cells). The outer portion of RANKL can be broken to form soluble RANKL (sRANKL) with a molecular weight of 31 kD. sRANKL is detectable in the circulatory system 49 Kiechl S et al found that the increased serum sRANKL levels in postmenopausal females were associated with breast cancer risk. Furthermore, serum RANKL is strongly associated with bone metastases from breast cancer, with significantly higher levels in patients with bone metastases compared to those with breast cancer. 50 Studies have also shown that RANKL (rs9533156) and OPG (rs3102735) polymorphisms are associated with bone metastases from breast cancer. 51

Osteoprotegerin

Osteoprotegerin (OPG) is a member of the tumour necrosis factor receptor superfamily and is a soluble, secreted glycoprotein. It is normally expressed by osteoblasts and bone marrow stromal cells. It is a multifunctional protein that is closely associated with bone remodelling, angiogenesis, immunomodulation and fibrosis. OPG competitively binds to RANKL on osteoblasts or stromal cells, thereby blocking RANKL-RANK interactions, making OPG a marker of bone formation. 52,53 Serum OPG is lower in patients with breast cancer bone metastases than in patients with primary breast cancer, and its level is negatively correlated with the number of metastatic lesions and the degree of bone destruction. The sensitivity and specificity of serum OPG for the diagnosis of bone metastases from breast cancer were 59 and 92%, respectively. The sensitivity and specificity of serum RANKL/OPG ratio in diagnosing bone metastases from breast cancer were 73 and 72%, respectively. Serum RANKL/OPG ratio was also found to be a predictor of bone metastasis in breast cancer. 54

Bone conversion markers

Bone turnover markers (BTM) are biochemical products that reflect the level of bone cell activity and bone matrix metabolism, and are usually divided into two categories: bone formation markers and bone resorption markers. In patients with bone metastases from breast cancer, the majority are osteolytic and mixed metastases, while osteogenic metastases are relatively uncommon.

The clinical role of BTM in breast cancer bone metastases is mainly in the following three areas (Table 3) 55 : (1) diagnosis. Lumachi F et al found that serum BALP, P1NP, CTX and TRACP-5b levels were associated with the development of bone metastases in breast cancer, and that the combination of BSAP, PINP and TRACP5b was more accurate for diagnosis. 56 (2) prognosis. Bone metastases from breast cancer can lead to the development of skeletal-related events (SREs), which in severe cases can lead to patient death. Urinary NTX levels are elevated in patients with SREs and death from breast cancer. 57 It was also found that patients with urinary NTX at baseline levels had a reduced risk of fracture and death. Serum BALP is also a predictor of bone metastases in breast cancer. 58 (3) Predicting Treatment Effectiveness. Both BALP and NTX can be used as predictors of the effectiveness of bone-targeting agent (BTA) therapy. 55

Table 3.

Clinical significance of bone turnover markers in bone metastases from breast cancer

Markers English and abbreviations Clinical significance
Bone formation markers
 Bone alkaline phosphatase Bone alkaline phosphatase, BALP Diagnosis and prognosis of bone metastases from breast cancer; prognosis of bone targeting agents (BTA)
 Type one pre-collagen N-terminal pre-peptide Pro-collagen Type 1 N-terminal pro-peptide, P1NP Diagnosis of bone metastases from breast cancer
 Type one pre-collagen C-terminal pre-peptide Pro-collagen Type 1 C-terminal pro-peptide, P1CP Diagnosis of bone metastases from breast cancer
Bone resorption markers
 Type one collagen N-terminal peptide C-telopeptide of Type one collagen, CTX Diagnosis of bone metastases from breast cancer
 Type one collagen N-terminal peptide N-telopeptide of Type one collagen, NTX Diagnosis and prognosis of bone metastases from breast cancer; prognosis of bone targeting agents (BTA)
 Deoxypyridinoline deoxypyridinoline, DPD Prediction and diagnosis of bone metastases from breast cancer
 Antitartrate acid phosphatase 5b Tartrate resistant acid phosphatase, TRACP-5b Diagnosis of bone metastases from breast cancer
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Conclusion

The measurement of biomarkers in patients' body fluids or tissues can help to predict, aid in the diagnosis and monitoring of bone metastases from breast cancer. Biomarker testing has certain advantages due to the ease of collection and low cost. Firstly, it is not yet possible to rely on these markers alone to locate bone metastases; secondly, the measurement values of some tumour markers may be biased by the effects of some drugs affecting bone metabolism and abnormal liver and kidney functions, and liquid biopsies such as CTCs need to ensure that the extracted cells and genes are sufficiently active. There are still many difficulties to overcome in terms of extraction techniques and analysis costs.

Footnotes

Funding: The study was supported by Natural Science Foundation of Hunan Province (No. 2020JJ4908).

Author Contribution Statement :Dongcheng Xu: Drafting of the article, critical review of the intellectual content of the article, supporting contribution; Mingxing Tang: Critical review of the intellectual content of the article, guidance, supporting contribution.

Contributor Information

Dongcheng Xu, Email: 736268337@qq.com.

Mingxing Tang, Email: Tangmingxing2018@163.com.

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