Bone Metastatic Breast Cancer Research Articles

The Marine Alga Sargassum horneri Is a Functional Food with High Bioactivity

Functional food factors can play a preventive and therapeutic role in several human diseases. The marine alga Sargassum horneri (S. horneri) has restorative effects in several types of metabolic disorders, including osteoporosis, diabetes, inflammatory conditions, and cancer cell growth. Osteoporosis is widely recognized as a major public health problem. Bone loss associated with ageing and diabetic states was prevented through the intake of bioactive compounds from S. horneri water extract in vivo by stimulating osteoblastic bone formation and inhibiting osteoclastic bone resorption in vitro. The intake of S. horneri water extract was found to have preventive effects on diabetic findings with an increase in serum glucose and lipid components. Furthermore, the S. horneri component has been shown to suppress adipogenesis from rat bone marrow cells and inflammatory conditions in vitro. Notably, the growth of bone metastatic human breast cancer MDA-MB-231 cells, which induce bone loss with osteolytic effects, was suppressed through culturing with the S. horneri water extract component in vitro. The S. horneri component, which has a molecular weight of less than 1000, was found to suppress the activation of NF-κB signaling by tumor necrosis factor-α, a cytokine associated with inflammation, in osteoblastic cells and macrophage RAW264.7 cells in vitro, suggesting a molecular mechanism. The bioactive component of S. horneri may play a multifunctional role in the prevention and treatment of metabolic disorders. This review outlines the advanced knowledge of the biological activity of the aqueous extract components of S. horneri and discusses the development of health supplements using this material.

#7. Downstream effects of Gli2 targeting on tumor-immune cell crosstalk in bone metastatic breast cancer

#7. Downstream effects of Gli2 targeting on tumor-immune cell crosstalk in bone metastatic breast cancer

#29. A novel control mechanism of endosomal trafficking in bone metastatic breast cancer cells

#29. A novel control mechanism of endosomal trafficking in bone metastatic breast cancer cells

#24. Mechanical loading-induced changes to the bone microenvironment control bone metastatic breast cancer lesions

#24. Mechanical loading-induced changes to the bone microenvironment control bone metastatic breast cancer lesions

Surgical Resection of Primary Tumor for Bone Metastatic Breast Cancer Patients at Initial Presentation.

The purpose of this study was to investigate whether primary tumor resection in patients with bone metastatic breast cancer has an impact on survival using the Surveillance, Epidemiology, and End Results database, considering subtype classification. We included all female patients with bone metastatic breast cancer at initial presentation between 2010 and 2016 with known hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) statuses. Cases showing unknown cause of death or unknown HR/HER2 status were excluded. Survival analysis was performed using Cox proportional hazards modeling to calculate hazard ratios (HZR). Of the 13,450 patients included in this study, 2,073 patients were HR+/HER2+, 8,597 patients were HR+/HER2-, 797 patients were HR-/HER2+, and 1,182 patients were HR-/HER2- (triple-negative). Five-year overall survival (OS) rate was 34.5% in HR+/HER2+, 26.0% in HR+/HER2-, 29.2% in HR-/HER2+ and 8.0% in triple-negative. Triple-negative patients showed the worsen OS [HR+/HER2+: HZR=2.1, 95% confidence interval (CI)=1.9-2.3; HR+/HER2-: HZR= 2.4, 95%CI=2.2-2.6; HR-/HER2+: HZR=1.5, 95%CI=1.3-1.6]. After excluding patients who died within six months, primary tumor resection prolonged survival in each subtype classification except HR-/HER2+. Patients with triple-negative bone metastatic breast cancer showed unfavorable survival. Primary tumor resection prolonged survival in each subtype except for HR-/HER2+.

A Representative Clinical Course of Progression, with Molecular Insights, of Hormone Receptor-Positive, HER2-Negative Bone Metastatic Breast Cancer.

Despite treatment advances, breast cancer remains a leading cause of death of women in the United States, mostly due to metastatic disease. Bone is a preferential site for breast cancer metastasis, and most metastatic breast cancer patients experience bone involvement at the time of death. The majority of patients with bone metastatic breast cancer are first diagnosed with and treated for early-stage disease, and from development of early-stage breast cancer to the recurrence of cancer in the bones, up to 30 years may elapse. Throughout this timeframe, a typical patient undergoes many treatments that have effects on the bone microenvironment. Therefore, this review explores the clinical course of a representative patient with hormone receptor-positive bone metastatic breast cancer, examining key treatment options at each stage and their effects on preventing and treating bone metastases.

Bisphosphonate-related Osteonecrosis of The Jaw : Is the Medication Duration Related to Advanced Disease Stage?

Abstract Objectives Osteonecrosis of the jaw (ONJ) is a serious adverse effect of therapy with bisphosphonates (BP) and other antiresorptive agents. The aim of the study was to report thirteen bisphosphonates related osteonecrosis of the jaw (BRONJ) patient cases at Kaohsiung Veterans General Hospital (VGHKS), Taiwan and their medical history and disease outcomes. Methods Thirteen symptomatic patients with BRONJ were reviewed between 1985 and 2021 at VGHKS. We included symptomatic patients who were in advanced BRONJ stage two and three. Four multiple myeloma, three bone metastatic breast cancer and six advanced osteoporosis patients. Results Seven patients were AAOMS MRONJ stage three and six were stage two. The average anti-resorptive medication duration was 25.83 ± 31.45 months in BRONJ stage two patients and 53.71 ± 31.25 months in BRONJ stage three patients respectively. No correlation was found between the anti-resorptive agent duration and BRONJ stage (p value = 0.098; Mann-Whitney U test) among cancer (p value = 0.157; Mann-Whitney U test) and osteoporosis patients (p value = 0.184; Mann-Whitney U test). Conclusion Most of them died of terminal stage cancer disease or complications of being bedridden. The correlation between the duration of anti-resorptive agents and BRONJ stage needs larger patient data to confirm the result.

Collagen Mineralization Decreases NK Cell-Mediated Cytotoxicity of Breast Cancer Cells via Increased Glycocalyx Thickness.

Skeletal metastasis is common in patients with advanced breast cancer and often caused by immune evasion of disseminated tumor cells (DTCs). In the skeleton, tumor cells not only disseminate to the bone marrow but also to osteogenic niches in which they interact with newly mineralizing bone extracellular matrix (ECM). However, it remains unclear how mineralization of collagen type I, the primary component of bone ECM, regulates tumor-immune cell interactions. Here, a combination of synthetic bone matrix models with controlled mineral content, nanoscale optical imaging, and flow cytometry are utilized to evaluate how collagen type I mineralization affects the biochemical and biophysical properties of the tumor cell glycocalyx, a dense layer of glycosylated proteins and lipids decorating their cell surface. These results suggest that collagen mineralization upregulates mucin-type O-glycosylation and sialylation by tumor cells, which increases their glycocalyx thickness while enhancing resistance to attack by natural killer (NK) cells. These changes are functionally linked as treatment with a sialylation inhibitor decreased mineralization-dependent glycocalyx thickness and made tumor cells more susceptible to NK cell attack. Together, these results suggest that interference with glycocalyx sialylation may represent a therapeutic strategy to enhance cancer immunotherapies targeting bone-metastatic breast cancer.

Osteoclast Cancer Cell Metabolic Cross-talk Confers PARP Inhibitor Resistance in Bone Metastatic Breast Cancer.

Metabolic interaction between osteoclasts and tumor cells contributes to resistance to DNA-damaging agents, which can be blocked by combination treatment with PARP and osteoclast inhibitors to reduce bone metastatic burden.

Golgi-triggered radiation sensitizer retention enhances the efferocytosis and immunotherapy in breast cancer with skeleton metastases

Radiotherapy with higher precision and better efficiency is required for breast cancer bone metastasis therapy. In this study, we synthesized a golgi-triggered radiation sensitizer, Furin Activated Iron Oxide nanoparticles (FAIOs), which could suppress breast cancer bone metastasis by targeting tumor micro-environment (TME) and enhancing immune response. As a multi-functional theranostic mediator, FAIOs enabled tumor-specific MRI and accurate radiation therapy in TMEs with enriched FURIN. The increased efferocytosis triggered by FAIOs-mediated tumor cell apoptosis offered remarkable benefits. Moreover, the osteoclast-mediated bone destruction was markedly alleviated. These encouraging findings provided insights into therapeutic and diagnostic value of these multifunctional FAIOs for bone-metastatic breast cancer. (Scheme)

Denosumab and Zoledronic Acid Differently Affect Circulating Immune Subsets: A Possible Role in the Onset of MRONJ.

This work investigated whether the anti-resorptive drugs (ARDs) zoledronic acid (Zol) and denosumab (Dmab) affect differently the levels of circulating immune cell subsets, possibly predicting the risk of developing medication-related ONJ (MRONJ) during the first 18 months of treatment. Blood samples were collected from 10 bone metastatic breast cancer patients receiving cyclin inhibitors at 0, 6, 12, and 18 months from the beginning of Dmab or Zol treatment. Eight breast cancer patients already diagnosed with MRONJ and treated with cyclin inhibitors and ARDs were in the control group. PBMCs were isolated; the trend of circulating immune subsets during the ARD treatment was monitored, and 12 pro-inflammatory cytokines were analyzed in sera using flow cytometry. In Dmab-treated patients, activated T cells were stable or increased, as were the levels of IL-12, TNF-α, GM-CSF, IL-5, and IL-10, sustaining them. In Zol-treated patients, CD8+T cells decreased, and the level of IFN-γ was undetectable. γδT cells were not altered in Dmab-treated patients, while they dramatically decreased in Zol-treated patients. In the MRONJ control group, Zol-ONJ patients showed a reduction in activated T cells and γδT cells compared to Dmab-ONJ patients. Dmab was less immunosuppressive than Zol, not affecting γδT cells and increasing activated T cells.

Prediction of bone metastasis risk of early breast cancer based on nomogram of clinicopathological characteristics and hematological parameters.

The purpose of this study was to determine the independent risk factors for bone metastasis in breast cancer and to establish a nomogram to predict the risk of bone metastasis in early stages through clinicopathological characteristics and hematological parameters. We selected 1042 patients with breast cancer from the database of Shandong Cancer Hospital for retrospective analysis, and determined independent risk factors for bone metastatic breast cancer (BMBC). A BMBC nomogram based on clinicopathological characteristics and hematological parameters was constructed using logistic regression analysis. The performance of the nomograph was evaluated using the receiver operating characteristic (ROC) and calibration curves. The clinical effect of risk stratification was tested using Kaplan-Meier analysis. BMBC patients were found to be at risk for eight independent risk factors based on multivariate analysis: age at diagnosis, lymphovascular invasion, pathological stage, pathological node stage, molecular subtype, platelet count/lymphocyte count, platelet count * neutrophil count/lymphocyte count ratio, Systemic Immunological Inflammation Index, and radiotherapy. The prediction accuracy of the BMBC nomogram was good. In the training set, the area under the ROC curve (AUC) was 0.909, and in the validation set, it was 0.926, which proved that our model had good calibration. The risk stratification system can analyze the risk of relapse in individuals into high- and low-risk groups. The proposed nomogram may predict the possibility of breast cancer bone metastasis, which will help clinicians optimize metastatic breast cancer treatment strategies and monitoring plans to provide patients with better treatment.

Dynamic regulation of drug biodistribution by turning tumors into decoys for biomimetic nanoplatform to enhance the chemotherapeutic efficacy of breast cancer with bone metastasis.

Breast cancer with bone metastasis accounts for serious cancer-associated pain which significantly reduces the quality of life of affected patients and promotes cancer progression. However, effective treatment using nanomedicine remains a formidable challenge owing to poor drug delivery efficiency to multiple cancer lesions and inappropriate management of cancer-associated pain. In this study, using engineered macrophage membrane (EMM) and drugs loaded nanoparticle, we constructed a biomimetic nanoplatform (EMM@DJHAD) for the concurrent therapy of bone metastatic breast cancer and associated pain. Tumor tropism inherited from EMM provided the targeting ability for both primary and metastatic lesions. Subsequently, the synergistic combination of decitabine and JTC801 boosted the lytic and inflammatory responses accompanied by a tumoricidal effect, which transformed the tumor into an ideal decoy for EMM, resulting in prolonged troop migration toward tumors. EMM@DJHAD exerted significant effects on tumor suppression and a pronounced analgesic effect by inhibiting µ-opioid receptors in bone metastasis mouse models. Moreover, the nanoplatform significantly reduced the severe toxicity induced by chemotherapy agents. Overall, this biomimetic nanoplatform with good biocompatibility may be used for the effective treatment of breast cancer with bone metastasis.

The Secretome of Parental and Bone Metastatic Breast Cancer Elicits Distinct Effects in Human Osteoclast Activity after Activation of β2 Adrenergic Signaling.

The sympathetic nervous system (SNS), particularly through the β2 adrenergic receptor (β2-AR), has been linked with breast cancer (BC) and the development of metastatic BC, specifically in the bone. Nevertheless, the potential clinical benefits of exploiting β2-AR antagonists as a treatment for BC and bone loss-associated symptoms remain controversial. In this work, we show that, when compared to control individuals, the epinephrine levels in a cohort of BC patients are augmented in both earlier and late stages of the disease. Furthermore, through a combination of proteomic profiling and functional in vitro studies with human osteoclasts and osteoblasts, we demonstrate that paracrine signaling from parental BC under β2-AR activation causes a robust decrease in human osteoclast differentiation and resorption activity, which is rescued in the presence of human osteoblasts. Conversely, metastatic bone tropic BC does not display this anti-osteoclastogenic effect. In conclusion, the observed changes in the proteomic profile of BC cells under β-AR activation that take place after metastatic dissemination, together with clinical data on epinephrine levels in BC patients, provided new insights on the sympathetic control of breast cancer and its implications on osteoclastic bone resorption.

Bone targeted miRNA delivery system for miR-34a with enhanced anti-tumor efficacy to bone-associated metastatic breast cancer

Bone metastatic cancer is the most common occurrence in breast cancer, and the treatment is also facing great challenges. MicroRNA-34a (miRNA-34a) is a promising anti-cancer miRNA for gene therapy to bone metastatic cancer patients. However, the lack of specificity to bone and low accumulation at the site of bone tumor remains the major challenge when used bone-associated tumor. To solve this problem, a bone-targeted vector for delivery of miR-34a to bone metastatic breast cancer was constructed by using the commonly used gene vector branched polyethylenimine 25 k (BPEI 25 k) as the skeleton and linking with alendronate (ALN) moieties for bone targeting group. The constructed gene delivery system PCA/miR-34a can efficiently prevent miR-34a from degradation during blood circulation and enhance the specific bone delivery and distribution. PCA/miR-34a nanoparticles can be uptake into tumor cells through clathrin and caveolae-mediated endocytosis, and directly regulate the expression of oncogenes, thus promoting tumor cell apoptosis and relieving bone tissue erosion. The results of experiments in vitro and in vivo confirmed that the constructed bone-targeted miRNA delivery system PCA/miR-34a can enhance the anti-tumor efficacy in bone metastatic cancer, and provide a potential strategy for gene therapy in bone metastatic cancer.

Select HDAC Inhibitors Enhance Osteolysis and Bone Metastasis Outgrowth but Can Be Mitigated With Bisphosphonate Therapy.

Breast cancer has a high predilection for spreading to bone with approximately 70% of patients who succumb to disease harboring bone disseminated tumor cells. Despite this high prevalence, treatments for bone metastatic breast cancer predominantly manage morbidities, including pain and hypercalcemia, rather than reducing bone metastasis incidence or growth. Histone deacetylase inhibitors (HDACi), including panobinostat, entinostat, and valproic acid, typically slow primary tumor progression and are currently in clinical trials for the treatment of many cancers, including primary and metastatic breast cancer, but their effects on bone metastatic disease have not been examined in preclinical models. We report that treatment with the HDACi panobinostat, but not entinostat or valproic acid, significantly reduced trabecular bone volume in tumor-naïve mice, consistent with previous reports of HDACi-induced bone loss. Surprisingly, treatment with entinostat or panobinostat, but not valproic acid, increased tumor burden and incidence in an experimental model of breast cancer bone metastasis. In vitro, multiple HDACi stimulated expression of pro-osteolytic genes in breast tumor cells, suggesting this may be a mechanism by which HDACi fuel tumor growth. In support of this, combination therapy of panobinostat or entinostat with the antiresorptive bisphosphonate zoledronic acid prevented bone metastatic progression; however, the addition of zoledronic acid to panobinostat therapy failed to fully correct panobinostat-induced bone loss. Together these data demonstrate that select HDACi fuel bone metastatic growth and provide potential mechanistic and therapeutic avenues to offset these effects. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

GLUT1-mediated magnetic liposomes for targeting bone metastatic breast cancer

Bone metastatic breast cancer is a malignant tumor in bone due to the metastasis of breast cancer, and its incidence is increasing worldwide. Treatment of cancer metastasized to bone is still a challenge because of the anticancer drugs lack target specificity. Finding an effective treatment for bone metastasis remains an urgent issue. In order to enhance the delivery of paclitaxel (PTX) to the bone metastases lesions, a novel glucose derivative was designed and synthesized in this work, which was used as liposome ligand to develop the magnetic liposome G-MLip (Glucose-modified magnetic liposome). The liposome could improve the drug formulations in the bone metastases mediated by glucose transporter 1 (GLUT1) and then target cancer cells. The PTX-loaded magnetic liposome PTX-G-MLip was prepared by the film hydration-ultrasound method. And the characterizations, such as size, zeta potential, encapsulation efficiency, release profile, stability, hemolysis, were well evaluated. What’s more, the enhanced target ability was also investigated in vitro and in mice. The metastatic bone-targeted capacity was confirmed that the PTX concentration from PTX-G-MLip in the bone metastases lesions was markedly increased in the presence of magnetic field (MF) compared with the free PTX and other liposomes. Inspired by the enhanced targeting ability, glucose-modified magnetic liposomes could serve as an effective drug delivery system for targeting and treating bone metastases.

Evaluation of the Effects of Ibandronic Acid and Zoledronic Acid on Progression-free Survival in Patients with Bone Metastatic Breast Cancer

Evaluation of the Effects of Ibandronic Acid and Zoledronic Acid on Progression-free Survival in Patients with Bone Metastatic Breast Cancer

Targeting SOST using a small-molecule compound retards breast cancer bone metastasis

BackgroundBreast cancer metastasis to the bone can be exacerbated by osteoporosis, is associated with poor long-term survival, and has limited therapeutic options. Sclerostin (SOST) is an endogenous inhibitor of bone formation, and an attractive target for treatment of osteoporosis. However, it is unclear whether SOST can be used as a therapeutic target for bone metastases of breast cancer, and whether small molecule compounds that target SOST in breast cancer cells can inhibit breast cancer bone metastasis.MethodsSOST expression in 442 breast cancer tissues was characterized by immunohistochemistry and statistically analyzed for the association with breast cancer bone metastases. Bone metastatic breast cancer SCP2 cells were induced for SOST silencing or overexpression and their bone metastatic behaviors were tested in vitro and in vivo. To identify potential therapeutics, we screened inhibitors of the interaction of SOST with STAT3 from a small chemical molecule library and tested the inhibitory effects of one inhibitor on breast cancer growth and bone metastasis in vitro and in vivo.ResultsWe found that up-regulated SOST expression was associated with breast cancer bone metastases and worse survival of breast cancer patients. SOST silencing significantly reduced the bone metastatic capacity of SCP2 cells. SOST interacted with STAT3 to enhance the TGF-β/KRAS signaling, increasing both tumor growth and bone metastasis. Treatment with one lead candidate, S6, significantly inhibited the growth of breast-cancer organoids and bone metastasis in mice.ConclusionsOur findings highlight a new class of potential therapeutics for treatment of bone metastasis in breast cancer.

A machine learning-Based model to predict early death among bone metastatic breast cancer patients: A large cohort of 16,189 patients.

Purpose: This study aims to develop a prediction model to categorize the risk of early death among breast cancer patients with bone metastases using machine learning models. Methods: This study examined 16,189 bone metastatic breast cancer patients between 2010 and 2019 from a large oncological database in the United States. The patients were divided into two groups at random in a 90:10 ratio. The majority of patients (n = 14,582, 90%) were served as the training group to train and optimize prediction models, whereas patients in the validation group (n = 1,607, 10%) were utilized to validate the prediction models. Four models were introduced in the study: the logistic regression model, gradient boosting tree model, decision tree model, and random forest model. Results: Early death accounted for 17.4% of all included patients. Multivariate analysis demonstrated that older age; a separated, divorced, or widowed marital status; nonmetropolitan counties; brain metastasis; liver metastasis; lung metastasis; and histologic type of unspecified neoplasms were significantly associated with more early death, whereas a lower grade, a positive estrogen receptor (ER) status, cancer-directed surgery, radiation, and chemotherapy were significantly the protective factors. For the purpose of developing prediction models, the 12 variables were used. Among all the four models, the gradient boosting tree had the greatest AUC [0.829, 95% confident interval (CI): 0.802-0.856], and the random forest (0.828, 95% CI: 0.801-0.855) and logistic regression (0.819, 95% CI: 0.791-0.847) models came in second and third, respectively. The discrimination slopes for the three models were 0.258, 0.223, and 0.240, respectively, and the corresponding accuracy rates were 0.801, 0.770, and 0.762, respectively. The Brier score of gradient boosting tree was the lowest (0.109), followed by the random forest (0.111) and logistic regression (0.112) models. Risk stratification showed that patients in the high-risk group (46.31%) had a greater six-fold chance of early death than those in the low-risk group (7.50%). Conclusion: The gradient boosting tree model demonstrates promising performance with favorable discrimination and calibration in the study, and this model can stratify the risk probability of early death among bone metastatic breast cancer patients.