Breast Cancer-induced Bone Metastasis Research Articles

Withaferin A inhibits breast cancer-induced osteoclast differentiation.

Bone is the most prone to metastatic spread of breast cancer cells for each subtype of the disease. Bone metastasis-related complications including severe pain and pathological fractures affect patients' quality of life. Current treatment options including surgery, radiation, and bone-targeted therapies (e.g., bisphosphonates) are costly or have serious adverse effects such as renal toxicity and osteonecrosis of the jaws. Therefore, a safe, inexpensive, and efficacious agent for prevention of breast cancer bone metastasis is urgently needed. Our previously published RNA sequencing analysis revealed that many genes implicated in bone remodeling and breast cancer bone metastasis were significantly downregulated by treatment with withaferin A (WA), which is a promising cancer chemopreventive agent derived from a medicinal plant (Withania somnifera). The present study investigated whether WA inhibits breast cancer induction of osteoclast differentiation. At plasma achievable doses, WA treatment inhibited osteoclast differentiation (osteoclastogenesis) induced by three different subtypes of breast cancer cells (MCF-7, SK-BR-3, and MDA-MB-231). WA and the root extract of W. somnifera were equally effective for inhibition of breast cancer induction of osteoclast differentiation. This inhibition was accompanied by suppression of interleukin (IL)-6, IL-8, and receptor activator of nuclear factor-κB ligand, which are pivotal osteoclastogenic cytokines. The expression of runt-related transcription factor 2, nuclear factor-κB, and SOX9 transcription factors, which positively regulate osteoclastogenesis, was decreased in WA-treated breast cancer cells as revealed by confocal microscopy and/or immunoblotting. Taken together, these data suggest that WA could be a promising agent for prevention of breast cancer-induced bone metastasis.

MicroRNA-506 ameliorates breast cancer-induced osteolytic bone metastasis via the NFATc-1 signaling pathway.

Breast cancer is becoming a common life-threatening disease, especially in women, along with higher incidence and mortality. MicroRNA (miR)-506 was reported to participate in breast cancer progression, while the role of miR-506 in breast cancer-induced osteolytic bone metastasis is unclear. In the present study, we found significant downregulation of miR-506 in breast cancer tissues and cell lines. Overexpression of miR-506 notably reduced the proliferative, migratory and invasive rates of MCF7 and MDA-MB-231 cells, and reduced the production of inflammatory factors IL-6 and TNF-α in MCF7 cells. Moreover, overexpression of miR-506 obviously inhibited tumor growth in an in vivo animal model. In addition, overexpression of miR-560 efficiently attenuated breast cancer-induced osteolysis in vivo, which was characterized by increased bone volume/total volume (BT/TV), trabecular number (Tb. N), and trabecular thickness (Tb. Th), as well as the reduced trabecular separation (Tb. Sp). The nuclear factor of activated T cell cytoplasmic 1 (NFATc1) was identified as a downstream target of miR-506, and overexpression of miR-506 could inhibit breast cancer progression by targeting NFATc1. Furthermore, our results showed that NFATc-1 might participate in the inhibition of miR-506 on breast cancer-induced osteolysis. In conclusion, our findings provide insights into understanding the pathogenesis of breast cancer and breast cancer-induced osteolytic bone metastasis, and miR-506 might serve as a novel biomarker for this disease.

A novel sulfate-bridged binuclear copper(ii) complex: structure, optical, ADMET andin vivoapproach in a murine model of bone metastasis

A novel complex, formulated as [Cu2(μ3-SO4)2(C4H6N2)4], showed significant ameliorative effects on tumor osteolytic lesions in malignant Walker 256/B breast cancer-induced bone metastases.

Cathepsin K and Its Specific Target in Mediating Breast Cancer Skeletal Metastasis

Cathepsin K (CTSK), a cysteine protease predominantly seen in osteoclasts, degrades protein present in the organic matrix of bone inducing bone resorption. Based on the accumulating evidences, CTSK has an established role in osteoclast mediated bone resorption, progression of cancer invasion, migration and extracellular matrix degradation through activating several pathways, which vary from other classes of cysteine proteinases such as Cathepsin B & L. Studies in the past have shown that CTSK is a key protease in breast cancer-induced bone metastases which are found highly expressed in human breast and prostate carcinomas. However, the involvement of CTSK in breast and prostate cancer development remains unclear. Bone is a key site of breast and prostate cancer metastasis and most patients with advanced disease encounter complications from incurable bone lesions. Therefore, CTSK can be viewed as an alternative target for treating patients with metastatic bone disease. This review discusses the molecular insights into CTSK and its specific targets in mediating breast cancer skeletal metastasis, so as to find the novelty of cathepsin K therapeutic target for the treatment of patients with osteolytic bone metastases.

Radiation therapy combined with bone-modifying agents ameliorates local control of osteolytic bone metastases in breast cancer.

Bone-modifying agents (BMAs) are frequently used for the treatment of bone metastases. Both BMA and radiation therapy (RT) are effective; however, there are few studies that have evaluated the efficacy of the combination treatment. We evaluated the effectiveness of RT + BMA in breast cancer-induced osteolytic bone metastasis as compared to BMA alone. A total of 43 lesions in 25 patients were evaluated. The median follow-up period was 18 (range, 2–90) months. None of the lesions was treated with chemotherapy or molecular targeted drugs during the follow-up period for evaluating the local response. Patients with complete or partial response were considered as responders, while those with stable or progressive disease were considered as non-responders. The rate of response with RT + BMA was significantly higher than that with BMA alone (P = 0.001). The cumulative incidence rate of response at 6 months was 54.4% in the RT + BMA group and 27.5% in the BMA alone group. The median time to response was 4 (range, 2–11) months in the RT + BMA group and 6 (range, 4–16) months in the BMA alone group. The overall survival rate in the responder group (83.1% at 1 year) was significantly higher than that in the non-responder group (37.5% at 1 year) (P = 0.029). In conclusion, RT combined with BMA was found to be more effective than BMA alone for the treatment of osteolytic bone metastasis, which thereby improves the prognosis.

Gö6983 attenuates breast cancer-induced osteolysis by the apoptotic pathway.

Bone metastasis caused by breast cancer leads to significant complications in treatment, and the resulting osteolysis considerably affects patients' overall survival and quality of life. Gö6983 is a broad spectrum protein kinase C inhibitor. In this study, based on our finding that the Gö6983 inhibits osteolysis, we applied Gö6983 to the MDA-MB-231 breast cancer-induced mouse bone metastasis model. And we found that Gö6983 has a strong inhibitory effect on the tumorigenic model of breast cancer by promoting the mitochondrial apoptosis pathway. Our study, therefore, demonstrates that Gö6983 has a potential inhibitory effect on breast cancer-induced osteoclast activation and provides mechanistic insight that may prove useful for designing future treatments.

Proanthocyanidins attenuate breast cancer-induced bone metastasis by inhibiting Irf-3/c-jun activation.

We have previously demonstrated the pivotal role of Jnk-mediated Irf-3/c-Jun in regulating nuclear factor kappa-Β ligand (RANKL)-induced osteoclastogenesis. Here, we demonstrated that proanthocyanidins (PACs) target Irf-3 to alleviate breast cancer-induced activation of osteoclasts. We also found that PACs induced apoptosis of osteoclast precursors by upregulating the ratio of bax/bcl-2 and activating caspase-3 activity. Such bone protective effect also could be observed in a bone metastasis model of breast cancer. These findings provided a novel therapeutic intervention targeting abnormal bone metabolism to alleviate bone metastasis of breast cancer.

Ordered arrangement of hydrated GdPO4 nanorods in magnetic chitosan matrix promotes tumor photothermal therapy and bone regeneration against breast cancer bone metastases

Surgical resection is a traditionally therapeutic strategy against breast cancer-induced bone metastases; however, it may cause cancer recurrence and local bone defects. Herein, Fe3O4 nanoparticles and hydrated GdPO4 nanorods were incorporated in bioactive chitosan (CS) matrix, forming multifunctional GdPO4/CS/Fe3O4 scaffolds for tumor photothermal therapy and bone tissue regeneration. The Fe3O4 nanoparticles in the GdPO4/CS/Fe3O4 scaffolds improved near-infrared (NIR) absorption capacity and photothermal conversion efficiency. Under the NIR laser irradiation, the local temperatures around the GdPO4/CS/Fe3O4 scaffolds were elevated high enough to stimulate the apoptosis of tumor cells, effectively avoiding postoperative cancer recurrence. The hydrated GdPO4 nanorods served as a novel bioactive component for enhanced angiogenesis and osteogenesis abilities. The as-released Gd3+ ions from the GdPO4/CS/Fe3O4 scaffolds induced the M2 polarization of macrophages for stabilizing as-formed vasculature. The newly formed blood vessels provided oxygen and nutrient for osteogenesis. Moreover, the hydrated GdPO4 nanorods in the scaffolds activated BMP-2/Smad/RUNX2 signaling pathway that facilitated cell proliferation, differentiation and bone tissue regeneration. Hence, the multifunctional GdPO4/CS/Fe3O4 scaffolds enable the photothermal ablation of postoperative residual tumors and subsequent bone defect healing, which may become a promising platform for the therapy of breast cancer bone metastases.

Incidence of skeletal-related events in patients with breast or prostate cancer-induced bone metastasis or multiple myeloma: A 12-year longitudinal nationwide healthcare database study

BackgroundThis study examined the incidence of skeletal-related events (SRE) among patients with breast cancer (BC)- or prostate cancer (PC)-induced bone metastasis or multiple myeloma (MM) based on a population-based, 12-year healthcare database. MethodsPatients aged ≥18 years with bone metastasis from BC or PC or with MM between 2004 and 2015 were included. SRE was defined as pathologic fracture, spinal cord compression, radiation, or surgery to bone. Patients were followed-up from the initial diagnosis of bone metastasis (for those with BC or PC) or MM until SRE occurrence. To estimate multiple SREs, we applied a 21-day time window to ensure that subsequent SREs occurred independently from the previous event. We calculated the incidence and 95% confidence intervals (CIs), stratified according to the previous SRE history. ResultsOur cohort included 53,231 patients, including 23,811 with BC, 19,170 with PC, and 10,250 with MM. The incidence of multiple SREs in the 21-day time window was 1.03 (95% CI = 1.01–1.05) in patients with previous SRE history and 0.19 (95% CI = 0.19–0.20) in those without. The cumulative SRE incidences were 47%, 31.4%, and 38.0% in BC, PC, and MM patients. ConclusionThe incidences of multiple SREs in BC- or PC-induced bone metastasis or MM in this 12-year South Korean cohort were slightly higher than those in European countries. Our study provided real-world evidence that patients with BC- or PC-induced bone metastasis or MM are at high risk of SRE.

Animal Models of Breast Cancer Bone Metastasis.

This chapter is designed to provide a comprehensive overview outlining the different in vivo models available for research into breast cancer bone metastasis. The main focus is to guide the researcher through the methodological processes required to establish and utilize these models within their own laboratory. These detailed methods are designed to enable the acquisition of accurate and meaningful results that can be used for publication and future translation into clinical benefit for women with breast cancer-induced bone metastasis.

Hypericin targets osteoclast and prevents breast cancer-induced bone metastasis via NFATc1 signaling pathway.

Bone is the most common target organ of metastasis of breast cancers. This produces considerable morbidity due to skeletal-related events, and severely reduces the quality of life. Increased osteoclast activity is implicated in breast cancer outgrowth in the bone microenvironment. Our previous observation of an anti-osteoclastic activity of hypericin, a natural plant compound, led us to investigate whether hypericin could inhibit bone metastasis and osteolysis caused by breast cancer. We find that hypericin inhibited the upregulation of osteoclasts stimulated by breast cancer cells. The activity of hypericin on osteoclasts and breast cancer-mediated osteoclastogenesis was associated with the inhibition of NFATc1 signaling pathway and attenuation of Ca2+ oscillation. Furthermore, hypericin suppresses invasion and migration in breast cancer cells, but has little effect on breast cancer-cell induced RANKL/OPG ratio in osteoblast or the expression of osteoclast-activating factors. Administration of hypericin could reduce tumor burden, osteolysis induced by direct inoculation of MDA-MB-231 cells into the bone marrow cavity of the tibia as well as metastasis of bone and improve survival in an experimental metastasis model by intracardiac injection of MDA-MB-231 breast cancer cells. Taken together, these results suggest that hypericin may be a potential natural agent for preventing and treating bone destruction in patients with bone metastasis due to breast cancer.

Mimicking breast cancer-induced bone metastasis in vivo: current transplantation models and advanced humanized strategies.

Bone metastasis is a complication that occurs in 80% of women with advanced breast cancer. Despite the prevalence of bone metastatic disease, the avenues for its clinical management are still restricted to palliative treatment options. In fact, the underlying mechanisms of breast cancer osteotropism have not yet been fully elucidated due to a lack of suitable in vivo models that are able to recapitulate the human disease. In this work, we review the current transplantation-based models to investigate breast cancer-induced bone metastasis and delineate the strengths and limitations of the use of different grafting techniques, tissue sources, and hosts. We further show that humanized xenograft models incorporating human cells or tissue grafts at the primary tumor site or the metastatic site mimic more closely the human disease. Tissue-engineered constructs are emerging as a reproducible alternative to recapitulate functional humanized tissues in these murine models. The development of advanced humanized animal models may provide better platforms to investigate the mutual interactions between human cancer cells and their microenvironment and ultimately improve the translation of preclinical drug trials to the clinic.

A tissue-engineered humanized xenograft model of human breast cancer metastasis to bone

ABSTRACTThe skeleton is a preferred homing site for breast cancer metastasis. To date, treatment options for patients with bone metastases are mostly palliative and the disease is still incurable. Indeed, key mechanisms involved in breast cancer osteotropism are still only partially understood due to the lack of suitable animal models to mimic metastasis of human tumor cells to a human bone microenvironment. In the presented study, we investigate the use of a human tissue-engineered bone construct to develop a humanized xenograft model of breast cancer-induced bone metastasis in a murine host. Primary human osteoblastic cell-seeded melt electrospun scaffolds in combination with recombinant human bone morphogenetic protein 7 were implanted subcutaneously in non-obese diabetic/severe combined immunodeficient mice. The tissue-engineered constructs led to the formation of a morphologically intact ‘organ’ bone incorporating a high amount of mineralized tissue, live osteocytes and bone marrow spaces. The newly formed bone was largely humanized, as indicated by the incorporation of human bone cells and human-derived matrix proteins. After intracardiac injection, the dissemination of luciferase-expressing human breast cancer cell lines to the humanized bone ossicles was detected by bioluminescent imaging. Histological analysis revealed the presence of metastases with clear osteolysis in the newly formed bone. Thus, human tissue-engineered bone constructs can be applied efficiently as a target tissue for human breast cancer cells injected into the blood circulation and replicate the osteolytic phenotype associated with breast cancer-induced bone lesions. In conclusion, we have developed an appropriate model for investigation of species-specific mechanisms of human breast cancer-related bone metastasis in vivo.

Andrographolide prevents human breast cancer-induced osteoclastic bone loss via attenuated RANKL signaling

Bone metastasis is a common and serious complication in advanced cancers such as breast cancer, prostate cancer, and multiple myeloma. Agents that prevent bone loss could be used to develop an alternative therapy for bone metastasis. RANKL, a member of the tumor necrosis factor superfamily, has been shown to play a significant role in cancer-associated bone loss. In this study, we examined the efficacy of the natural compound andrographolide (AP), a diterpenoid lactone isolated from the traditional Chinese and Indian medicinal plant Andrographis paniculata, in reducing breast cancer-induced osteolysis. AP prevented human breast cancer-induced bone loss by suppressing RANKL-mediated and human breast cancer cell-induced osteoclast differentiation. Molecular analysis revealed that AP prevented osteoclast function by inhibiting RANKL-induced NF-κB and ERK signaling pathway in lower dose (20 μM), as well as inducing apoptosis at higher dose (40 μM). Thus, AP is a potent inhibitor of breast cancer-induced bone metastasis.

Pro‐osteolytic effects of chronic morphine administration in a model of breast cancer‐induced bone pain.

Many common cancers have a high propensity for bone metastasis; for breast cancer, bone metastasis affects 70% of advanced patients and is the most common site for secondary tumor relapse. Tumor manifestation disrupts bone homeostasis and results in debilitating chronic skeletal pain that decreases patient functional status, quality of life and survival. Morphine remains the golden standard for managing cancer‐induced bone pain; however, opioids including morphine are associated with a host of side effects that complicate chronic dosing schedules. Furthermore, it has been posited that morphine may accelerate bone wasting in patients; in models of secondary bone metastasis, morphine exacerbates fracture rate, markers of osteolysis, and pain behaviors.We sought to determine whether morphine exacerbates bone loss in the 66.1‐Balb/C model of breast cancer‐induced bone metastasis (BCBM). Sham and tumor‐inoculated animals received a constant morphine infusion for 7 days (20 mg/kg/day). Morphine produced initial analgesia but failed to manage behaviors indicative of cancer‐induced bone pain over time; additionally, morphine treatment increased TRACP 5b in sera and RANKL in femur extrudate, suggesting that morphine enhances osteolysis in BCBM. In vitro studies evaluated the ability of morphine to induce osteoclastogenesis in the presence of permissive levels of RANKL. Morphine did not appear to affect tumor burden in vivo or in vitro viability of tumor cells. These data suggest that morphine worsens bone loss in the 66.1‐Balb/C model and may act directly on osteoclast cells; however, the exact mechanism of morphine‐induced bone loss is unknown and remains a barrier to improving pain relief in suffering BCBM patients.

Plumbagin Inhibits Osteoclastogenesis and Reduces Human Breast Cancer-Induced Osteolytic Bone Metastasis in Mice through Suppression of RANKL Signaling

Bone loss is one of the major complications of advanced cancers such as breast cancer, prostate cancer, and multiple myeloma; agents that can suppress this bone loss have therapeutic potential. Extensive research within the last decade has revealed that RANKL, a member of the tumor necrosis factor superfamily, plays a major role in cancer-associated bone resorption and thus is a therapeutic target. We investigated the potential of vitamin K3 analogue plumbagin (derived from Chitrak, an Ayurvedic medicinal plant) to modulate RANKL signaling, osteoclastogenesis, and breast cancer-induced osteolysis. Plumbagin suppressed RANKL-induced NF-κB activation in mouse monocytes, an osteoclast precursor cell, through sequential inhibition of activation of IκBα kinase, IκBα phosphorylation, and IκBα degradation. Plumbagin also suppressed differentiation of these cells into osteoclasts induced either by RANKL or by human breast cancer or human multiple myeloma cells. When examined for its ability to prevent human breast cancer-induced bone loss in animals, plumbagin (2 mg/kg body weight) administered via the intraperitoneal route significantly decreased osteolytic lesions, resulting in preservation of bone volume in nude mice bearing human breast tumors. Overall, our results indicate that plumbagin, a vitamin K analogue, is a potent inhibitor of osteoclastogenesis induced by tumor cells and of breast cancer-induced osteolytic metastasis through suppression of RANKL signaling.

Variability of the paracrine‐induced osteoclastogenesis by human breast cancer cell lines

Breast cancer frequently metastasizes to the bone, often leading to the formation of osteolytic lesions. This work compares the paracrine-induced osteoclastogenesis mediated by four human breast cancer cell lines, the estrogen-receptor positive T47D and MCF-7 and the estrogen-negative SK-BR-3 and Hs-578T cell lines. Human osteoclast precursor cells were cultured in the presence of conditioned media from the breast cancer cell lines (10% and 20%), collected at different culture periods (48 h, 7 days, and 14 days). Cultures performed in the absence or the presence of M-CSF and RANKL served as negative and positive control, respectively. Results showed that the cell lines differentially expressed several osteoclastogenic genes. All cell lines exhibited a significant osteoclastogenic potential, evidenced by a high TRAP activity and number of osteoclastic cells, expression of several osteoclast-related genes, and, particularly, a high calcium phosphate resorption activity. Differences among the osteoclastogenic potential of the cell lines were noted. T47D and MCF-7 cell lines displayed the highest and the lowest osteoclastogenic response, respectively. Despite the variability observed, MEK and NF-κB signaling pathways, and, at a lesser extent, PGE2 production, seemed to have a central role on the observed osteoclastogenic response. In conclusion, the tested breast cancer cell lines exhibited a high osteoclastogenic potential, although with some variability on the cell response profile, a factor to be considered in the development of new therapeutic approaches for breast cancer-induced bone metastasis.

Abstract 1753: Comparison between early versus delayed treatment of breast cancer induced osteolytic bone metastasis by TGFβ inhibitors in a murine model

Abstract In breast cancer patients the preferential metastasis to bone often causes considerable morbidity and mortality. Timely intervention is needed for the prevention and treatment of breast cancer-induced bone metastasis and osteolysis. Increased TGFβ signaling has been implicated to promote cancer cell invasion to bone and cause osteolysis. In this study we have evaluated the efficacy of the early and delayed start of treatment by TGFβ antagonists, TGFβ R1 kinase inhibitor (TβRI) and soluble TGFβ type III receptor (sRIII), in a murine bone metastasis model utilizing human breast cancer cells. The female athymic nude mice injected intracardiacally with human breast cancer MDA-MB-231 cells were divided into five groups (n=10). In the two early treatment groups, the i.p. treatment started on the same day of tumor cell inoculation and in the two delayed treatment groups, treatment started on the 8th day after tumor cell inoculation with TβRI (20 µg/mice) and sRIII (100 µg/mice) respectively and continued every alternate day. Control group of animals were injected with phosphate buffered saline. The experiment was terminated after 25 days. The incidence of osteolytic metastasis determined by Faxitron X-Ray of the legs and tumor burden by the histology of tibia was remarkably reduced in the early treatment group in comparison to the control group. On the other hand, the delayed start of the treatment showed little effect on the reduction of tumor burden and bone loss indicating better efficacy of early treatment by TGFβ inhibitors in preventing homing of the tumor cells into the bone. As a potential mechanism, we have investigated the role of TGFβ inhibitors in vitro on the bone marrow mesenchymal stem cell (BM-MSC) induced cancer cell invasion which has been implicated to facilitate early entry of breast cancer cell into bone marrow. We have observed that the medium conditioned by BM-MSCs stimulated the invasion of MDA-MB-231 cells, which was significantly inhibited by TGFβ antagonists. Our results point to the possible therapeutic utility of TGFβ inhibitors to prevent primarily the initiation of breast cancer-induced bone metastasis by the inhibition of homing of the tumor cells into the bone. The mechanism may involve the modulation of the bone marrow mesenchymal stem cell microenvironment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1753. doi:10.1158/1538-7445.AM2011-1753

Abstract P5-03-01: Role of Aromatase and Its Inhibitor in Breast Cancer-Induced Tumorigenesis and Bone Metastasis

Abstract Aromatase (Aro) is the rate-limiting enzyme that catalyzes the final step in estrogen (E2) biosynthesis. An important strategy to treat hormone-dependent BCa is suppression of estrogen receptor (ER) action by antiestrogens or aromatase inhibitors (AI). Letrozole is a very specific and potent AI. In postmenopausal women, the ovaries cease to make E2 but concentration of E2 in their BCa tissue are maintained at a certain level for survival and proliferation of BCa cells, which is dependent on local E2 formation catalyzed by Aro. Although BCa cells have been shown to express Aro, the local E2 is largely produced by adipose stromal cells in the breast. This raises the question of how ER positive (ER+) metastatic BCa cells survive after they enter blood circulation, where E2 level is very low. We cultured human ER+ BCa CAMA-1, Aro-transfected MCF-7 and ZR-75-1 (ZR) cells in suspension to mimic circulating BCa cells. Interestingly, suspension culture increased Aro expression, suggesting circulating ER+ BCa may up-regulate intracrine E2 activity for survival after leaving the E2-rich adipose stroma at primary site. The expression of Aro also enhances cell proliferation and supplementation of testosterone (T), the substrate of Aro, stimulates this proliferation further. Notably, while these cells show an increased rate of apoptosis in suspension than in adherent culture, addition of T in suspension culture significantly suppressed the rate of apoptosis and addition of letrozole blocked the T-induced cell survival in suspension culture. To investigate the importance of intracrine E2 in promoting tumorigenesis and metastasis, we implanted Aro-expressing ZR cells orthotopically and intracardiacally (I.C.) into female athymic mice; vector-transfected ZR cells were used as control. While control ZR cells were incapable of forming tumors without E2 supplementation, Aro-expressing cells generated orthotopic tumors with no E2 supplementation after 3-weeks of inoculation. More interestingly, mice with I.C. inoculated Aro-expressing cells also presented distant bone metastasis in the mandible and tibiae/femora after 2-weeks of inoculation, detected by whole mouse fluorescence and bioluminescence imaging as the cells were stably transfected with a luciferase and GFP expression vector. To determine whether growth of orthotopic tumors can be inhibited by systemic administration of an AI, we treated the mice in one group with letrozole at 10 mg/mouse/day and the other group with the vehicle as control after the average tumor volume reached 150 mm3. After 3-weeks, the tumor burden in the letrozole treatment group reduced significantly while tumor burden in the control group increased continuously. Our studies show that suspension culture increases expression of Aro mRNA in several ER+ BCa cell lines, which likely results in increased intracrine E2 signaling and contributes to the survival of these BCa cellsin suspension. This provides a mechanistic insight into how ER+ BCa cells may survive the low E2 condition in circulation and subsequently induce distant metastasis as observed in the I.C. model. Our study provides an important foundation for future investigation on how hormone-dependent BCa cells up-regulate Aro expression in circulation and induce bone metastasis. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-03-01.

Source and significance of circulating fibronectin in breast cancer-induced bone metastasis

Source and significance of circulating fibronectin in breast cancer-induced bone metastasis