Breast Cancer Bone Metastasis Research Articles

Molecular insights into the interplay between adiposity, breast cancer and bone metastasis.

Cancer is a complex disease, with various pre-existing health ailments enhancing its pathology. In cancer, the extracellular environment contains various intrinsic physiological factors whose levels are altered with aging and pre-existing conditions. In obesity, the tumor microenvironment and metastases are enriched with factors that are both derived locally, and from other physiological compartments. Similarly, in obesity, the cancer cell environment both at the site of origin and at the secondary site i.e., metastatic niche, contains significantly more phenotypically-altered adipocytes than that of un-obese cancer patients. Indeed, obesity has been linked with cancer progression, metastasis, and therapy resistance. Adipocytes not only interact with tumor cells, but also with adjacent stromal cells at primary and metastatic sites. This review emphasizes the importance of bidirectional interactions between adipocytes and breast tumor cells in breast cancer progression and its bone metastases. This paper not only chronicles the role of various adipocyte-derived factors in tumor growth, but also describes the significance of adipocyte-derived bone metastatic factors in the development of bone metastasis of breast cancer. It provides a molecular view of the interplay between the adipocytes and tumor cells involved in breast cancer bone metastasis. However, more research is needed to determine if targeting cancer-associated adipocytes holds promise as a potential therapeutic approach for breast cancer bone metastasis treatment. Interplay between adipocytes and breast cancer cells at primary cancer site and metastatic bone microenvironment. AMSC Adipose-derived mesenchymal stem cell, CAA Cancer associated adipocytes, CAF Cancer associated fibroblast, BMSC Bone marrow derived mesenchymal stem cell, BMA Bone marrow adipocyte.

Abstract PS17-48: Potential role of activated leukocyte cell adhesion molecule (ALCAM) in hepatocyte growth factor (HGF) signalling in vascular endothelial cells and implications in breast cancer

Abstract Background. Activated Leukocyte Cell Adhesion Molecule, ALCAM (also known as CD166) is a member of the immunoglobulin superfamily and a cell surface adhesion molecule involved in heterophilic and homophilic interactions during cell-cell adhesion in epithelial cells, cancer cells and endothelial cells. ALCAM appears to be linked to tumour progression in a number of cancers including breast cancer, though there are conflicting reports as to its precise prognostic implications and significance. We have previously reported that ALCAM has a tumour suppressive role in breast cancer and is inversely correlated with clinical outcome (1) and interestingly bone metastasis of breast cancer (2). We have also reported that ALCAM has a diverse role in other cell types including keratinocytes and endothelial cells. In the present study, we investigated the association between ALCAM and hepatocyte growth factor (HGF)/cMET, a signalling pathway established as a key promoter of cancer progression, influencing both the aggressive nature of cancer cells and acting as an angiogenic and lymphangiogenic factor, in breast cancer and endothelial cells. Methods. The expression pattern and correlation of ALCAM, HGF and cMET in human breast cancer were deduced from a clinical breast cancer cohort. ALCAM manipulated HECV cell lines, previously established in our laboratories, were used in conjunction with recombinant human HGF and cMET inhibitors to assess cellular functions and the implications of this relationship at a cellular level. Results. We compared the expression of ALCAM with that of HGF and cMET within the breast cancer cohort and found that ALCAM/CD166 showed a highly significant negative correlation with the HGF receptor cMET (r=-0.17, p<0.0001) and a weak negative correlation with HGF, although this was not significant. ALCAM was not found to correlate with its heterophilic partner CD6. In previously generated HECV models, ALCAM manipulation showed a marked influence on cellular function and responsiveness to HGF treatment. Discussion. ALCAM’s role in breast cancer progression and related mechanisms is complex. Our current data suggests this may involve an interaction with the cMET/HGF signalling pathway and may also impact the endothelial component within the tumour microenvironment to influence disease progression. Reference1 King JA, Ofori-Acquah SF, Stevens T, et al. Activated leukocyte cell adhesion molecule in breast cancer: prognostic indicator. Breast Cancer Res. 2004;6:R478-87. Reference2 Davies SR, Dent C, Watkins G et al. Expression of the cell to cell adhesion molecule, ALCAM, in breast cancer patients and the potential link with skeletal metastasis. Oncol Rep. 2008;19:555-61. Citation Format: Andrew James Sanders, David Guo Jiang, Jianyuan Zeng, Robert Edward Mansel, Eleri Davies, Amber Xinyu Li, Keith Gordon Harding, Wen Guo Jiang. Potential role of activated leukocyte cell adhesion molecule (ALCAM) in hepatocyte growth factor (HGF) signalling in vascular endothelial cells and implications in breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-48.

Abstract PS17-41: In depth single cell profiling of a case of bone metastases with associated organoid models reveals a precision medicine approach to treatment

Abstract Occurring in 65-80% of metastatic breast cancer (BC), bone metastasis (BoM) is the major cause of BC related mortality. Under current standard of care, 5 year overall survival for patients with BoM is 20-25%, warranting the need of improved treatments. Like other cancers, BC BoM has high inter- and intra-patient heterogeneity. Thus, understanding disease evolution and heterogeneity of BoM at the individual patient level will be key to guide precise application of targeted therapies. In this study, we describe in depth histologic and single cell molecular characterization of a case of invasive lobular breast cancer (ILC) metastasis to bone. We collected fixed primary tumor (ER+/PR-/HER2- ILC) and fresh pelvis and tibia BoMs from a patient. H&E/IHC staining and whole exome sequencing (WES) of DNA and RNA of the samples were performed. Organoids were derived from the two BoMs and single cell RNA sequencing was applied to these cultures and the BoMs. Based on H&E/IHC staining, this case evolved from a ER+ primary ILC to ER- BoM with mixed lobular and ductal carcinoma features. WES revealed 208 missense somatic mutations in the BoMs. 15 were predicted as BC drivers, two of which are druggable including PIK3CA (E545K) and BRCA1 (D1834H, H399P). Notably, BRCA1 (D1834H) was not found in the primary tumor. Based on RNA sequencing, estrogen signaling was downregulated, while TGF-β, Wnt beta catenin and PI3K signaling, epithelial to mesenchymal transition (EMT) and angiogenesis were upregulated, all of which have been reported to be potential targets in BoMs. scRNAseq of BoMs revealed 5 major cell populations and pronounced heterogeneity. The two BoMs showed similar cellular compositions, including epithelial (30-50%), fibroblasts (50%), immune (5-10%), osteoclasts (1-2%) and endothelial cells (1-2%). Within epithelial cells, there were 5 major clusters exhibiting unique transcriptomic features, including a TNF-α signaling high cluster, two clusters showing high partial EMT (pEMT) signatures majorly regulated by PRRX1/2, TWIST1/2, and FOXS1, a cluster in active cell proliferation, and a cluster showing high signatures related to endocrine resistance. In fibroblasts, 3 clusters were identified representing ECM remodeling, angiogenesis (VEGFA high) and myofibroblasts. Immune cells majorly composed of macrophages, CD4+, CD8+ and Treg T cells. 2.2% tumor and 3.2% T cells express PDL1, exceeding the 1% threshold to select patients eligible for anti-PDL1 therapy. Based on CellPhoneDB, epithelial cells with high pEMT signature show the most interactions and uniquely interact with Treg cells through TNFSF4-TNFRSF4 which has been reported to promote Treg cell proliferation, and is investigated in clinic for immune therapy. Organoids were developed to evaluate therapeutic potential of targetable mutations, upregulated genes and susceptible cell populations. WES showed organoids preserved the mutational signatures of the matched tumor. scRNAseq showed all epithelial populations in the tumor were preserved in the matched organoids at comparable abundance. Consistent with the BRCA1 and PIK3CA mutations, organids were responsive to a PARP (Talazoparib: IC50 1.3uM/1.3uM) and PI3K (Alpelisib: IC50 9uM/4uM) inhibitor. We are currently examining the therapeutic potential of inhibiting pEMT, TNF-α, and genes upregulated in BoM. In summary, we have demonstrated a precision medicine approach to understand the evolution and heterogeneity of BC BoM. We have identified potential therapeutic targets and evaluated those in patient-specific organoids, thereby providing insights for the design of a precision medicine based clinical treatment strategy. Citation Format: Kai Ding, Fangyuan Chen, Nolan Priedigkeit, Daniel D. Brown, Tanya Heim, Rebecca Watters, Kurt Weiss, Jennifer Atkinson, Steffi Oesterreich, Adrian Lee. In depth single cell profiling of a case of bone metastases with associated organoid models reveals a precision medicine approach to treatment [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-41.

Abstract PS14-14: Distinct tumor microenvironments of breast cancer bone metastases in pre- and post-menopausal patients

Abstract Breast cancer (BC) patient prognosis has improved over the past 2 decades with a 99% 5 year survival rate for localized BC, yet metastatic BC continues to cause high mortality with a 5 year survival rate of 27%. Recent advances have been made in the treatment of primary BC, providing an opportunity to apply this positive momentum towards treating metastatic disease. Approximately 70% of BC metastases occur in the bone, with the majority of patients retaining estrogen receptor positive (ER+) disease. The BC tumor microenvironment (TME) in bone exhibits an osteolytic bone pathology of bone destruction and is composed of primarily four cellular groups including the cancer, immune, vascular and bone cells. These cellular constituents are uniquely responsive to estradiol (E2) and exhibit unique TMEs dependent on menopause status, when circulating E2 is lost. Both menopause and BC endocrine therapies induce an E2-deprived post-menopausal state in patients. However, studying the distinctions of pre- and post-menopausal BC patient TMEs is still necessary to understand how natural menopause status impacts non-treatment naïve ER+ BC that is already in a therapy induced menopausal state. In particular the full extent of the unique phenotypes harbored by pre- versus post-menopausal ER+ BC tumor induced bone disease (TIBD) remains unknown, and elucidation of these difference may identify novel mechanisms of TIBD. We investigated a cohort of demineralized formalin-fixed and paraffin-embedded (FFPE) pre- and post-menopausal lytic bone metastasis biopsies from non-treatment naïve ER+ BC patients. We utilized immunohistochemistry (IHC), NanoString nCounter gene expression panels and GeoMx Digital Spatial Profiling (DSP) to observe distinct TMEs in our archival biopsy cohort. IHC staining of pre- and post-menopausal samples displayed alterations to immune cell infiltration and composition. Differential gene expression analysis revealed enrichment of myeloid function in pre-menopausal patients compared to post-menopausal patients. Alterations to immune signaling pathways and cell profiles were also exhibited in pre-menopausal patients compared to post-menopausal patients. DSP analysis presented changes in both the tumor and microenvironment, and unique immune cell infiltration with checkpoint proteins in both pre-menopausal and post-menopausal ER+ BC bone metastases. The identification of these targetable markers unique to pre- and post-menopausal TIBD could provide new therapeutic strategies for ER+ BC patients with bone lesions. Thus, we propose that bone biopsies could be performed to guide selection for metastatic BC patients into appropriate therapeutic interventions, with pre- and post-menopausal patients receiving tailored treatments based on their distinct protein and RNA expression of available therapies. This personalized approach to treating metastatic disease could enhance patient quality of life and survival. Citation Format: Claire Ihle, Meredith Provera, Desiree Straign, Katy Zolman, Erin Smith, Adrie Van Bokhoven, Scott Lucia, Philip Owens. Distinct tumor microenvironments of breast cancer bone metastases in pre- and post-menopausal patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS14-14.

CXCR4 and RANK Combination as a Predictor of Breast Cancer Bone Metastasis in Indonesia

Abdominal wall reconstruction and hernia repair surgery continue to evolve with the intention to successfully repair the abdominal wall,

CXCR4 and RANK Combination as a Predictor of Breast Cancer Bone Metastasis in Indonesia

CXCR4 and RANK Combination as a Predictor of Breast Cancer Bone Metastasis in Indonesia

Osteoclast-derived small extracellular vesicles induce osteogenic differentiation via inhibiting ARHGAP1

Activated osteoclasts release large amounts of small extracellular vesicles (sEVs) during bone remodeling. However, little is known about whether osteoclast-derived sEVs affect surrounding cells. In this study, osteoclasts were generated by stimulating bone marrow macrophages (BMMs) with macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear actor κB ligand (RANKL). We performed microarray analysis of sEV-microRNAs (miRNAs)s secreted from osteoclast at different stages and identified four miRNAs that were highly expressed in mature osteoclast-derived sEVs. One of these miRNAs, miR-324, significantly induced osteogenic differentiation and mineralization of primary mesenchymal stem cells (MSCs) in vitro by targeting ARHGAP1, a negative regulator of osteogenic differentiation. We next fabricated an sEV-modified scaffold by coating decalcified bone matrix (DBM) with osteoclast-derived sEVs, and the pro-osteogenic regeneration activities of the sEV-modified scaffold were validated in a mouse calvarial defect model. Notably, miR-324-enriched sEV-modified scaffold showed the highest capacity on bone regeneration, whereas inhibition of miR-324 in sEVs abrogated these effects. Taken together, our findings suggest that miR-324-contained sEVs released from mature osteoclast play an essential role in the regulation of osteogenic differentiation and potentially bridge the coupling between osteoclasts and MSCs.

Multiphysics simulation of a compression-perfusion combined bioreactor to predict the mechanical microenvironment during bone metastatic breast cancer loading experiments.

Incurable breast cancer bone metastasis causes widespread bone loss, resulting in fragility, pain, increased fracture risk, and ultimately increased patient mortality. Increased mechanical signals in the skeleton are anabolic and protect against bone loss, and they may also do so during osteolytic bone metastasis. Skeletal mechanical signals include interdependent tissue deformations and interstitial fluid flow, but how metastatic tumor cells respond to each of these individual signals remains underinvestigated, a barrier to translation to the clinic. To delineate their respective roles, we report computed estimates of the internal mechanical field of a bone mimetic scaffold undergoing combinations of high and low compression and perfusion using multiphysics simulations. Simulations were conducted in advance of multimodal loading bioreactor experiments with bone metastatic breast cancer cells to ensure that mechanical stimuli occurring internally were physiological and anabolic. Our results show that mechanical stimuli throughout the scaffold were within the anabolic range of bone cells in all loading configurations, were homogenously distributed throughout, and that combined high magnitude compression and perfusion synergized to produce the largest wall shear stresses within the scaffold. These simulations, when combined with experiments, will shed light on how increased mechanical loading in the skeleton may confer anti-tumorigenic effects during metastasis.

Matrix Metalloproteinase 13 Inhibitors for Modulation of Osteoclastogenesis: Enhancement of Solubility and Stability.

Matrix metalloproteinase 13 (MMP-13) activity has been correlated to breast cancer bone metastasis. It has been proposed that MMP-13 contributes to bone metastasis through the promotion of osteoclastogenesis. To explore the mechanisms of MMP-13 action, we previously described a highly efficacious and selective MMP-13 inhibitor, RF036. Unfortunately, further pursuit of RF036 as a probe of MMP-13 in vitro and in vivo activities was not practical due to the limited solubility and stability of the inhibitor. Our new study has explored replacing the RF036 backbone sulfur atom and terminal methyl group to create inhibitors with more favorable pharmacokinetic properties. One compound, designated inhibitor 3, in which the backbone sulfur and terminal methyl group of RF036 were replaced by nitrogen and oxetane, respectively, had comparable activity, selectivity, and membrane permeability to RF036, while exhibiting greatly enhanced solubility and stability. Inhibitor 3 effectively inhibited MMP-13-mediated osteoclastogenesis but spared collagenolysis, and thus represents a next-generation MMP-13 probe applicable for in vivo studies of breast cancer metastasis.

Clinicopathologic features of single bone metastasis in breast cancer.

The most common site for metastasis in patients with breast cancer is the bone. In this case series, we investigated patients whose surgical and medical treatment for primary breast cancer was conducted at our center and first disease recurrence was limited to only 1 bone.We analyzed 910 breast cancer patients, 863 had no metastasis and 47 cases had a single bone metastasis ≥ 6 months after their first diagnosis. Demographic, epidemiological, histopathological and intrinsic tumor subtype differences between the non-metastatic group and the group with solitary bone metastases and their statistical significance were examined. Among established breast cancer risk factors, we studied twenty-nine variables.Three variables (Type of tumor surgery, TNM Stage III tumors and mixed type (invasive ductalcarsinoma + invasive lobular carcinoma) histology) were significant in multivariate logistic regression analysis. Accordingly, the risk of developing single bone metastasis was approximately 15 times higher in patients who underwent mastectomy and 4.8 and 2.8 times higher in those with TNM Stage III tumors and with mixed type (invasive ductal carcinoma + invasive lobular carcinoma) histology, respectively.In conclusion, the risk of developing single bone metastasis is likely in non-metastatic patients with Stage III tumors and possibly in mixed type tumors. Knowing this risk, especially in patients with mixed type tumors, may be instrumental in taking measures with different adjuvant therapies in future studies. Among these, treatment modalities such as prolonged hormone therapy and addition of bisphosphonates to the adjuvant treatments of stage III and mixed breast cancer patients may be considered.

Bone metastases induce metabolic changes and mitophagy in mice.

What is the central question of this study? Cachexia causes severe changes in skeletal muscle metabolism and function and is a key predictor of negative outcomes in cancer patients: what are the changes in whole animal energy metabolism and mitochondria in skeletal muscle? What is the main finding and its importance? There is decreased whole animal energy expenditure in mice with cachexia. They displayed highly dysmorphic mitochondria and mitophagy in skeletal muscle. Cachexia causes changes in skeletal muscle metabolism. Mice with MDA-MB-231 breast cancer bone metastases and cachexia have decreased whole animal energy metabolism and increased skeletal muscle mitophagy. We examined whole animal energy metabolism by indirect calorimetry in mice with MDA-MB-231 breast cancer bone metastases, and showed decreased energy expenditure. We also examined skeletal muscle mitochondria and found that mitochondria in mice with MDA-MB-231 bone metastases are highly dysmorphic and have altered protein markers of mitochondrial biogenesis and dynamics. In addition, LC3B protein was increased in mitochondria of skeletal muscle from cachectic mice, and colocalized with the mitochondrial protein Tom20. Our data demonstrate the importance of mitophagy in cachexia. Understanding these changes will help contribute to defining treatments for cancer cachexia.

Bone targeting nano-aggregates prepared from self-assembled polyaspartamide graft copolymers for pH sensitive DOX delivery.

Nanoparticles with bone targeting ability and pH-sensitivity were prepared with polyaspartamide (PASPAM) derivatives based on polysuccinimide (PSI) grafted with octadecylamine (C18), hydrazine (HYD) and polyethylene glycol (PEG, Mw: 5000). For the bone targeting, alendronate (ALN), which has bone affinity, was grafted to PEG and doxorubicin (DOX) was conjugated with linkers of acid sensitive hydrazone bonds, which can be cleaved most effectively in an intracellular acidic environment. At pH 5.0, ∼75% of the drug was released from ALN-PEG/C18/HYD-DOX-g-PASPAM due to the effective cleavage of HYD under the acidic condition. Also, ALN-PEG/C18/HYD-DOX-g-PASPAM particles were more effectively adsorbed on the surface of bone than PEG/C18/HYD-DOX-g-PASPAM. According to an in vivo antitumor activity test, the volume of tumor treated with ALN-PEG/C18/HYD-DOX-g-PASPAM decreased (1550 mm3) when compared with the PBS control sample (3850 mm3), proving that ALN-PEG/C18/HYD-DOX-g-PASPAM is an effective drug delivery system for the treatment of bone metastasis of breast cancer.

Breast cancer exosomes contribute to pre-metastatic niche formation and promote bone metastasis of tumor cells.

Rationale: Breast cancer preferentially develops osteolytic bone metastasis, which makes patients suffer from pain, fractures and spinal cord compression. Accumulating evidences have shown that exosomes play an irreplaceable role in pre-metastatic niche formation as a communication messenger. However, the function of exosomes secreted by breast cancer cells remains incompletely understood in bone metastasis of breast cancer.Methods: Mouse xenograft models and intravenous injection of exosomes were applied for analyzing the role of breast cancer cell-derived exosomes in vivo. Effects of exosomes secreted by the mildly metastatic MDA231 and its subline SCP28 with highly metastatic ability on osteoclasts formation were confirmed by TRAP staining, ELISA, microcomputed tomography, histomorphometric analyses, and pit formation assay. The candidate exosomal miRNAs for promoting osteoclastogenesis were globally screened by RNA-seq. qRT-PCR, western blot, confocal microscopy, and RNA interfering were performed to validate the function of exosomal miRNA.Results: Implantation of SCP28 tumor cells in situ leads to increased osteoclast activity and reduced bone density, which contributes to the formation of pre-metastatic niche for tumor cells. We found SCP28 cells-secreted exosomes are critical factors in promoting osteoclast differentiation and activation, which consequently accelerates bone lesion to reconstruct microenvironment for bone metastasis. Mechanistically, exosomal miR-21 derived from SCP28 cells facilitates osteoclastogenesis through regulating PDCD4 protein levels. Moreover, miR-21 level in serum exosomes of breast cancer patients with bone metastasis is significantly higher than that in other subpopulations.Conclusion: Our results indicate that breast cancer cell-derived exosomes play an important role in promoting breast cancer bone metastasis, which is associated with the formation of pre-metastatic niche via transferring miR-21 to osteoclasts. The data from patient samples further reflect the significance of miR-21 as a potential target for clinical diagnosis and treatment of breast cancer bone metastasis.

CST6 protein and peptides inhibit breast cancer bone metastasis by suppressing CTSB activity and osteoclastogenesis.

Background: Bone metastasis is a frequent symptom of breast cancer and current targeted therapy has limited efficacy. Osteoclasts play critical roles to drive osteolysis and metastatic outgrowth of tumor cells in bone. Previously we identified CST6 as a secretory protein significantly downregulated in bone-metastatic breast cancer cells. Functional analysis showed that CST6 suppresses breast-to-bone metastasis in animal models. However, the functional mechanism and therapeutic potential of CST6 in bone metastasis is unknown.Methods: Using in vitro osteoclastogenesis and in vivo metastasis assays, we studied the effect and mechanism of extracellular CST6 protein in suppressing osteoclastic niches and bone metastasis of breast cancer. A number of peptides containing the functional domain of CST6 were screened to inhibit bone metastasis. The efficacy, stability and toxicity of CST6 recombinant protein and peptides were evaluated in preclinical metastasis models.Results: We show here that CST6 inhibits osteolytic bone metastasis by inhibiting osteoclastogenesis. Cancer cell-derived CST6 enters osteoclasts by endocytosis and suppresses the cysteine protease CTSB, leading to up-regulation of the CTSB hydrolytic substrate SPHK1. SPHK1 suppresses osteoclast maturation by inhibiting the RANKL-induced p38 activation. Importantly, recombinant CST6 protein effectively suppresses bone metastasis in vitro and in vivo. We further identified several peptides mimicking the function of CST6 to suppress cancer cell-induced osteoclastogenesis and bone metastasis. Pre-clinical analyses of CTS6 recombinant protein and peptides demonstrated their potentials in treatment of breast cancer bone metastasis.Conclusion: These findings reveal the CST6-CTSB-SPHK1 signaling axis in osteoclast differentiation and provide a promising approach to treat bone diseases with CST6-based peptides.

Carbonic anhydrase 13 suppresses bone metastasis in breast cancer

Metastatic progression is the leading cause of mortality in breast cancer. However, molecular mechanisms that govern this process remain unclear. In this study, we found that carbonic anhydrase 13 (CA13) plays a potential role in suppressing bone metastasis. iRFP713-labeled iCSCL-10A (iRFP-iCSCL-10A) breast cancer cells, which exhibit the hallmarks of cancer stem cells, exerted the ability of bone metastasis in hind legs after 5-week injections, whereas no metastasis was observed in control iRFP713-labeled MCF-10A (iRFP-MCF10A) cells. Transcriptome analysis indicated that the expression of several genes, including metabolism-related CA13, was reduced in bone metastatic iRFP-iCSCL-10A cells. In vitro and in vivo analyses demonstrated that overexpression of CA13 in iRFP-iCSCL-10A cells suppressed migration, invasion, and bone metastasis, together with the reduction of VEGF-A and M-CSF expression. Furthermore, we found that breast cancer patients with a low CA13 expression had significantly shorter overall survival and disease-free survival rates compared to those with higher CA13 expression. These findings suggest that CA13 may act as a novel prognostic biomarker and would be a therapeutic candidate for the prevention of bone metastasis in breast cancer.

Prognosis prediction model for patients with breast cancer with bone metastasis: based on a population database

Background: Prognosis prediction for breast cancer bone metastasis (BCBM) patients is related to the development of further treatment options, and the judgment of prognosis is often not determined by one factor, which requires a comprehensive assessment of the patient’s condition.

More than 10-years survival despite bilateral breast cancer and multiple bone metastasis: a case report

Although the recent advances in the management of breast cancer and the reported increased survival rates over the past years, the disease still constitutes a significant burden on patients and healthcare systems. To enhance the survival rates of patients with breast cancer, improved treatment modalities and early detection of the malignancy are two key elements to achieve this goal. We aim to present a case that was previously diagnosed with bilateral breast cancer, together with multiple bony masses and survived for more than 20 years after the administration of certain treatment regimens. We have discussed the management approaches that were administered to this patient, which calls for future investigations to study the efficacy of these management modalities in enhancing the outcomes of similar cases.

Asparagine Endopeptidase Inhibitor Can Prevent Breast Cancer Bone Metastasis by Attenuating Osteoclast Differentiation and Function

Asparagine Endopeptidase Inhibitor Can Prevent Breast Cancer Bone Metastasis by Attenuating Osteoclast Differentiation and Function

Chinese expert consensus statement on the clinical diagnosis and treatment of breast cancer bone metastasis and bone related disease

: Breast cancer is one of the most common malignancy in Chinese women. Up to 80% of patients with metastatic breast cancer develop bone metastasis resulting in local bone destruction and skeletal-related events such as pathological fracture and spinal cord compression. Skeletal-related events pose an enormous impact on patients' motor function and quality of life. Therefore, prevention of skeletal-related events is one of the treatment objectives of breast cancer bone metastasis, which often requires participation of multidisciplinary team to optimize therapeutic regimen for individual. Standard anti-tumor therapy includes chemotherapy, endocrine therapy, targeted therapy, immunotherapy, etc. Bone-modifying agents are the basic treatment after the occurrence of bone metastases in addition to anti-tumor therapy. As the disease progresses, patients may receive bone radiotherapy and orthopedic surgery. The purpose of this expert’s consensus is to standardize diagnosis and treatment of breast cancer bone metastasis and improve the quality of life of patients.

Construction and validation of a 6-gene nomogram discriminating lung metastasis risk of breast cancer patients.

Breast cancer is the most common malignant disease in women. Metastasis is the foremost cause of death. Breast tumor cells have a proclivity to metastasize to specific organs. The lung is one of the most common sites of breast cancer metastasis. Therefore, we aimed to build a useful and convenient prediction tool based on several genes that may affect lung metastasis-free survival (LMFS). We preliminarily identified 319 genes associated with lung metastasis in the training set GSE5327 (n = 58). Enrichment analysis of GO functions and KEGG pathways was conducted based on these genes. The best genes for modeling were selected using a robust likelihood-based survival modeling approach: GOLGB1, TMEM158, CXCL8, MCM5, HIF1AN, and TSPAN31. A prognostic nomogram for predicting lung metastasis in breast cancer was developed based on these six genes. The effectiveness of the nomogram was evaluated in the training set GSE5327 and the validation set GSE2603. Both the internal validation and the external validation manifested the effectiveness of our 6-gene prognostic nomogram in predicting the lung metastasis risk of breast cancer patients. On the other hand, in the validation set GSE2603, we found that neither the six genes in the nomogram nor the risk predicted by the nomogram were associated with bone metastasis of breast cancer, preliminarily suggesting that these genes and nomogram were specifically associated with lung metastasis of breast cancer. What’s more, five genes in the nomogram were significantly differentially expressed between breast cancer and normal breast tissues in the TIMER database. In conclusion, we constructed a new and convenient prediction model based on 6 genes that showed practical value in predicting the lung metastasis risk for clinical breast cancer patients. In addition, some of these genes could be treated as potential metastasis biomarkers for antimetastatic therapy in breast cancer. The evolution of this nomogram will provide a good reference for the prediction of tumor metastasis to other specific organs.