Nuclear Factor-κB–Dependent Mechanisms in Breast Cancer Cells Regulate Tumor Burden and Osteolysis in Bone

Gordon, Andrew H.; O’Keefe, Regis J.; Schwarz, Edward M.; Rosier, Randy N.; Puzas, J. Edward

doi:10.1158/0008-5472.can-04-4017

Cited by 31 publications

(16 citation statements)

References 56 publications

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“…Results from the histomorphometric analysis indicated that there was a significant reduction in trabecular bone area in the presence of MDA-MB-231 cells at 36 days post-injection and that the extent of bone loss increased with time; which supports the findings of previous studies [13,34] where a decrease in trabecular bone area was observed following intratibial implantation of MDA-MB-231 cells. Our results also indicate that significant evidence of bone loss only occurred following two bone remodelling cycles, given that there was no significant reduction in %Tb.Ar in the cancer-injected limb at 18 days post-injection.…”

Section: Discussionsupporting

confidence: 88%

Breast Cancer Cells Induce Osteolytic Bone Lesions In vivo through a Reduction in Osteoblast Activity in Mice

et al. 2013

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Bone metastases are severely debilitating and have a significant impact on the quality of life of women with metastatic breast cancer. Treatment options are limited and in order to develop more targeted therapies, improved understanding of the complex mechanisms that lead to bone lesion development are warranted. Interestingly, whilst prostate-derived bone metastases are characterised by mixed or osteoblastic lesions, breast-derived bone metastases are characterised by osteolytic lesions, suggesting unique regulatory patterns. This study aimed to measure the changes in bone formation and bone resorption activity at two time-points (18 and 36 days) during development of the bone lesion following intratibial injection of MDA-MB-231 human breast cancer cells into the left tibiae of Severely Combined Immuno-Deficient (SCID) mice. The contralateral tibia was used as a control. Tibiae were extracted and processed for undecalcified histomorphometric analysis. We provide evidence that the early bone loss observed following exposure to MDA-MB-231 cells was due to a significant reduction in mineral apposition rate, rather than increased levels of bone resorption. This suggests that osteoblast activity was impaired in the presence of breast cancer cells, contrary to previous reports of osteoclast-dependent bone loss. Furthermore mRNA expression of Dickkopf Homolog 1 (DKK-1) and Noggin were confirmed in the MDA-MB-231 cell line, both of which antagonise osteoblast regulatory pathways. The observed bone loss following injection of cancer cells was due to an overall thinning of the trabecular bone struts rather than perforation of the bone tissue matrix (as measured by trabecular width and trabecular separation, respectively), suggesting an opportunity to reverse the cancer-induced bone changes. These novel insights into the mechanisms through which osteolytic bone lesions develop may be important in the development of new treatment strategies for metastatic breast cancer patients.

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Section: Discussionsupporting

confidence: 88%

Breast Cancer Cells Induce Osteolytic Bone Lesions In vivo through a Reduction in Osteoblast Activity in Mice

et al. 2013

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“…The RANKL-RANK signaling axis is important at the tumorbone interface in the differentiation and activation of osteoclasts (3,9,(21)(22)(23)(24). Osteoclasts are major producers of MMP9 (25)(26)(27)(28)(29).…”

Section: Discussionmentioning

confidence: 99%

Cathepsin G–Mediated Activation of Pro–Matrix Metalloproteinase 9 at the Tumor-Bone Interface Promotes Transforming Growth Factor-β Signaling and Bone Destruction

Wilson

Nannuru

Singh

2009

Molecular Cancer Research

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Increased transforming growth factor-β (TGF-β) signaling has been observed at the tumor-bone interface of mammary tumor-induced osteolytic lesions despite no observed transcriptional up-regulation of TGF-β. To this point, the mechanism for enhanced TGF-β signaling remains unclear. The bulk of TGF-β that is released at the tumor-bone interface is in an inactive form secondary to association with β-latency-associated protein and latency TGF-β binding protein. We hypothesized that the observed increase in TGF-β signaling is due to increased cathepsin G-dependent, matrix metalloproteinase 9 (MMP9)-mediated activation of latent TGF-β. MMP9 is capable of activating latent TGF-β, and we observed that decreased production of MMP9 was associated with reduced TGF-β signaling. Similar to TGF-β, MMP9 is released in an inactive form and requires proteolytic activation. We showed that cathepsin G, which we have previously shown to be up-regulated at the tumor-bone interface, is capable of activating pro-MMP9. Inhibition of cathepsin G in vivo significantly reduced MMP9 activity, increased the ratio of latent TGF-β to active TGF-β, and reduced the level of TGF-β signaling. Our proposed model based on these results is that cathepsin G is up-regulated through tumor-stromal interactions and activates pro-MMP9, active MMP9 cleaves and releases active TGF-β, and active TGF-β can then promote tumor growth and enhance osteoclast activation and subsequent bone resorption. Thus, for the first time, we have identified cathepsin G and MMP9 as proteases involved in enhanced TGF-β signaling at the tumor-bone interface of mammary tumor-induced osteolytic lesions and have identified these proteases as potential therapeutic targets.

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“…Blockade of NF-kB signaling in MDA-MB-231 cells by the mutant IkappaB decreased in vitro cell proliferation (Gordon and O'Keefe, 2005). Proliferation and activation of bronchial epithelial cells are also associated with activation of the NF-kB signal (Vignola and Chiappara, 2001).…”

Section: Induction Of Cell Growth and Inhibition Of Apoptosis In Humamentioning

confidence: 99%

Fibronectin induces cell proliferation and inhibits apoptosis in human bronchial epithelial cells: pro-oncogenic effects mediated by PI3-kinase and NF-κB

2006

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The extracellular matrix glycoprotein, fibronectin, influences a variety of cellular functions including adhesion, migration, survival, differentiation, and growth. Fibronectin has also been shown to increase the migration and proliferation of human lung carcinoma cells. However, the role of fibronectin in controlling lung airway epithelial cell phenotype remains unknown. Here, we demonstrate that fibronectin stimulates the proliferation of human bronchial epithelial cells (BEAS-2B and 16-HBE). Of note, fibronectin induced the mRNA and protein expression of c-Myc and cyclin D1, while it decreased the expressions of cyclin-dependent kinase inhibitor p21WAF-1/CIP1/MDA-6 (p21) and the tumor suppressor gene phosphatase and tensin homolog deleted on chromosome ten (PTEN). Fibronectin also stimulated the phosphorylation of the phosphatidylinositol 3 kinase (PI3-K) downstream signal Akt. The inhibitor of PI3-K, Wortmannin, and anti-a5b1 integrin antibodies abrogated the effect of fibronectin on c-Myc, cyclin D1, p21, and PTEN expression. The stimulatory effect of fibronectin was mediated by nuclear factor kappaB (NF-jB) since fibronectin induced the expression of the p65 component of NF-jB and enhanced NF-jB DNA binding. Furthermore, we found that p65 small interfering RNA inhibited the effect of fibronectin on c-Myc, cyclin D1, p21, PTEN expression, and on fibronectin-induced cell proliferation. Finally, we found that fibronectin inhibits apoptosis by reducing DNA fragmentation and inhibiting the activities of caspases 3/7. Taken together, our findings demonstrate that fibronectin stimulates human bronchial epithelial cell growth and inhibits apoptosis through activation of NF-jB, which, in turn, increases the expression of c-Myc and cyclin D1 and decreases p21 and PTEN via a5b1 integrin-dependent signals that include PI3-K/Akt. Therefore, alternations in the extracellular matrix composition of the lung, with increased fibronectin, might promote epithelial cell growth and thereby contribute to oncogenesis in certain settings.

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Nuclear Factor-κB–Dependent Mechanisms in Breast Cancer Cells Regulate Tumor Burden and Osteolysis in Bone

Cited by 31 publications

References 56 publications

Breast Cancer Cells Induce Osteolytic Bone Lesions In vivo through a Reduction in Osteoblast Activity in Mice

Breast Cancer Cells Induce Osteolytic Bone Lesions In vivo through a Reduction in Osteoblast Activity in Mice

Cathepsin G–Mediated Activation of Pro–Matrix Metalloproteinase 9 at the Tumor-Bone Interface Promotes Transforming Growth Factor-β Signaling and Bone Destruction

Fibronectin induces cell proliferation and inhibits apoptosis in human bronchial epithelial cells: pro-oncogenic effects mediated by PI3-kinase and NF-κB

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