Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0153690 (bone metastases)
 6,382 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Parathyroid hormone-related protein (PTH-rP) was purified and cloned 10 years ago as a factor responsible for the hypercalcemia associated with malignancy. Clinical evidence supports another important role for PTH-rP in malignancy as a mediator of the bone destruction associated with osteolytic metastasis. Patients with PTH-rP positive breast carcinoma are more likely to develop bone metastasis. In addition, breast carcinoma metastatic to bone expresses PTH-rP in >90% of cases, compared with only 17% of metastasis to nonbone sites. These observations suggest that PTH-rP expression by breast carcinoma cells may provide a selective growth advantage in bone due to its ability to stimulate osteoclastic bone resorption. Furthermore, growth factors such as transforming growth factor-beta (TGF-beta), which are abundant in bone matrix, are released and activated by osteoclastic bone resorption and may enhance PTH-rP expression and tumor cell growth. To investigate the role of PTH-rP in the pathophysiology of breast carcinoma metastasis to bone, the human breast carcinoma cell line MDA-MB-231 was studied in a murine model of human breast carcinoma metastasis to bone. A series of experiments were performed in which 1) PTH-rP secretion was altered, 2) the effects of PTH-rP were neutralized, or 3) the responsiveness to TGF-beta was abolished in MDA-MB-231 cells. Cultured MDA-MB-231 cells secreted low amounts of PTH-rP that increased fivefold in response to TGF-beta. Tumor cells inoculated into the left cardiac ventricle of nude mice caused osteolytic metastasis similar to that observed in humans with breast carcinoma. When PTH-rP was overexpressed in the tumor cells, bone metastases were increased. MDA-MB-231 cells transfected with the cDNA for human preproPTH-rP secreted a tenfold greater amount of PTH-rP and caused significantly greater bone metastases when inoculated into the left cardiac ventricle of female nude mice compared with parental cells. In contrast, when the biologic effects of PTH-rP were neutralized or its production was suppressed, such metastases were decreased. Treatment of mice with a neutralizing monoclonal antibody to human PTH-rP resulted in a decrease in the development and progression of bone metastasis due to the parental MDA-MB-231 cells. Similar results were observed when mice were treated with dexamethasone, a potent glucocorticoid that suppresses production of PTH-rP by the MDA-MB-231 cells in vitro. The role of bone-derived TGF-beta in the development and progression of bone metastasis was studied by transfecting MDA-MB-231 cells with a cDNA encoding a TGF-beta type II receptor lacking a cytoplasmic domain, which acts as a dominant negative to block the cellular response to TGF-beta. Stable clones expressing this mutant receptor (MDA/TbetaRIIdeltacyt) did not increase PTH-rP secretion in response to TGF-beta stimulation compared with controls of untransfected MDA-MB-231 or those transfected with the empty vector. Mice inoculated into the left cardiac ventricle with MDA/TbetaRIIdeltacyt had fewer and smaller bone metastases as assessed radiographically and histomorphometrically compared with controls. Taken together, these data suggest that PTH-rP expression by breast carcinoma cells enhance the development and progression of breast carcinoma metastasis to bone. Furthermore, TGF-beta responsiveness of breast carcinoma cells may be important for the expression of PTH-rP in bone and the development of osteolytic bone metastasis in vivo. These interactions define a critical feedback loop between breast carcinoma cells and the bone microenvironment that may be responsible for the alacrity with which breast carcinoma grows in bone.
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PMID:Parathyroid hormone-related protein and bone metastases. 936 24

A significant percentage (50-70%) of patients with metastatic breast carcinoma (MBC) will have disease involving the bony skeleton. Clonal selection mediated by parathyroid hormone-related protein and other factors may explain the high incidence of osseous metastases in MBC. The presence of specific growth factors and cytokines in the microenvironment of bone may contribute to the successful establishment and growth of metastatic lesions and also might determine response or resistance of these lesions to chemotherapy or hormonal therapy. Osteolytic bone lesions in MBC frequently give rise to serious clinical problems including bone pain, pathologic fracture, hypercalcemia, and neurologic complications. MBC often is treated with systemic chemotherapy or hormonal therapy. The purpose of this article was to review the recent published literature describing the impact of systemic chemotherapy and hormonal therapy of MBC on the response of bone lesions and their clinical course and complications. Evaluating the response of bone lesions can be problematic and may be complicated by the phenomenon of "tumor flare" that may be observed with either chemotherapy or hormonal therapy. Use of the International Union Against Cancer criteria for the response of bone lesions is recommended. Several studies report objective responses (20-60%) of lytic bone metastases to standard combination chemotherapy regimens such as cyclophosphamide, methotrexate, and 5-fluorouracil and cyclophosphamide, doxorubicin, and 5-fluorouracil, mitoxantrone and 5-FU, newer combinations, and single agents including paclitaxel and docitaxel but responses to vinorelbine may be less frequent. Complete responses of bone lesions to chemotherapy are rare but partial responses and disease stabilization can lead to long term patient benefit. A series from the M. D. Anderson Cancer Center of patients with bone metastases treated with 5-FU, doxorubicin, and cyclophosphamide chemotherapy reported a median duration of response of 14 months. In a recent multicenter study of 195 patients with lytic lesions from MBC treated with chemotherapy, the objective response rate (complete response + partial response) in bone was 18% and 65% of the patients developed at least 1 morbid skeletal event with a median onset of 7.0 months from the start of chemotherapy. Hormone-dependent breast carcinoma has a proclivity to metastasize to bone. In earlier studies comparing aminoglutethimide or medroxyprogesterone acetate with tamoxifen, a higher response rate of bone metastases was observed for the first two agents. However, in more recent studies comparing newer aromatase inhibitors, such as anastrozole, fadrozole, and letrozole, with megestrol acetate, there were no significant differences in rates of response in bone. Patients with MBC with bony lesions respond to both chemotherapy and hormonal therapy and can have a prolonged survival. Therefore such patients are in a more favorable position to benefit from adjunctive supportive therapy such as bisphosphonates intended to reduce skeletal morbidity.
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PMID:Issues concerning the role of chemotherapy and hormonal therapy of bone metastases from breast carcinoma. 936 31

Hypercalcemia is a common paraneoplastic syndrome due to the secretion by tumors of parathyroid hormone-related protein (PTHrP) and/or other osteolytic factors. In the present study, we have measured plasma PTHrP using two immunoradiometric assays for PTHrP, assay N (Nichols) and assay I (INCSTAR), recognizing the 1-86 domain of PTHrP, for the evaluation of malignancy-associated hypercalcemia. The study included 25 tumor patients with hypercalcemia (HCa) [corrected serum calcium (SCa) > or = 2.70 mmol/L], 20 normocalcemic patients with cancer (NCa), and ten healthy control subjects. Plasma PTHrP was either undetectable or within the respective normal range in the majority of NCa patients and in the control subjects, with both assays. Plasma PTHrP was increased in 13 and 15 of HCa cases with assay N and assay I, respectively. PTHrP was elevated in plasma in 5/6 (assay N) and 3/6 (assay I) HCa patients with squamous tumors. However, plasma PTHrP was high in only 2/9 (assay N) and 1/9 (assay I) HCa cases with hematological tumors. Less than 40% of HCa patients with bone metastases, and >75% of those without bone involvement, had elevated plasma PTHrP with both assays. Detectable plasma PTHrP and SCa were significantly correlated using assay N (p = 0.025) and assay I (p = 0.01), in the HCa group. A highly significant correlation (p <0.001) was found between detectable plasma PTHrP with both assays, and a high agreement between them based on simple kappa statistics (p < 0.001), in the latter group. Our results indicate that each assay may be similarly useful in detecting PTHrP hyperproduction in cancer patients.
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PMID:Comparison of two immunoradiometric assays for parathyroid hormone-related protein in the evaluation of cancer patients with and without hypercalcemia. 985

Breast cancer frequently metastasizes to the skeleton, and the associated bone destruction is mediated by the osteoclast. Growth factors, including transforming growth factor-beta (TGF-beta), released from bone matrix by the action of osteoclasts, may foster metastatic growth. Because TGF-beta inhibits growth of epithelial cells, and carcinoma cells are often defective in TGF-beta responses, any role of TGF-beta in metastasis is likely to be mediated by effects on the surrounding normal tissue. However, we present evidence that TGF-beta promotes breast cancer metastasis by acting directly on the tumor cells. Expression of a dominant-negative mutant (TbetaRIIDeltacyt) of the TGF-beta type II receptor rendered the human breast cancer cell line MDA-MB-231 unresponsive to TGF-beta. In a murine model of bone metastases, expression of TbetaRIIDeltacyt by MDA-MB-231 resulted in less bone destruction, less tumor with fewer associated osteoclasts, and prolonged survival compared with controls. Reversal of the dominant-negative signaling blockade by expression of a constitutively active TGF-beta type I receptor in the breast cancer cells increased tumor production of parathyroid hormone-related protein (PTHrP), enhanced osteolytic bone metastasis, and decreased survival. Transfection of MDA-MB-231 cells that expressed the dominant-negative TbetaRIIDeltacyt with the cDNA for PTHrP resulted in constitutive tumor PTHrP production and accelerated bone metastases. These data demonstrate an important role for TGF-beta in the development of breast cancer metastasis to bone, via the TGF-beta receptor-mediated signaling pathway in tumor cells, and suggest that the bone destruction is mediated by PTHrP.
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PMID:TGF-beta signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. 991 31

We analyzed the use of different promoters and the splicing patterns of the exons encoding 5'- and 3'-untranslated sequence amounts of parathyroid hormone-related protein (PTHrP) gene products in breast cancers. Tumor samples from 74 cases of primary breast cancer that had been followed from 1 to 14 years were selected retrospectively according to the occurrence of metastasis: 18 patients developed no metastasis (NM), 56 developed metastases (M), 22 of whom developed metastases in soft tissues (MB-) and 34 of whom developed bone metastases (MB+). The amount of the 1-139 isoform mRNA was much higher in the tumors of patients who later developed metastases (M: 0.29 +/- 0.03) than in those of patients who developed no metastases (NM, 0.13 +/- 0.03; p < 0.01). This isoform mRNA was also more abundant in breast tumors from patients who developed bone metastases (MB+, 0.39 +/- 0.04) than in those of patients who developed metastases in soft tissues (MB-, 0.15 +/- 0.03; p < 0. 0001). By contrast, the amounts of the 1-141 isoform mRNA in these three groups of tumors were similar, but its concentration was higher in the tumors of premenopausal women than in those of postmenopausal women (p < 0.05). Analysis with 5' untranslated regions-specific primers showed transcription from all three putative transcription start sites of PTHrP (P1, P2, and P3). The P3-initiated transcripts were more abundant in patients who developed metastases (M, 0.31 +/- 0.03) than in the nonmetastatic tumors (NM, 0.13 +/- 0.03; p < 0.01). The amount of P3 element did not differ with the site of metastasis (BM+, 0.32 +/- 0.05; BM-, 0. 28 +/- 0.05; NS). The same trend was observed for the P2 element. However, the use of P2-initiated messages was strongly associated with the absence of estrogen receptors from the breast tumors (p < 0. 01). We thus find a close association between the pattern of PTHrP gene expression and the outcome of breast cancer. The P3-initiated start site and the presence of PTHrP 139 mRNA could help identify patients at risk of developing metastases.
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PMID:The parathyroid hormone-related protein (PTHrP) gene: use of downstream TATA promotor and PTHrP 1-139 coding pathways in primary breast cancers vary with the occurrence of bone metastasis. 1002 5

Parathyroid hormone-related protein (PTHrP) was originally identified as the tumor factor responsible for a clinical syndrome known as humoral hypercalcemia of malignancy. It is now appreciated that PTHrP3 is a developmental regulatory molecule expressed during the formation of a wide variety of organs. Recently, our laboratory has demonstrated that PTHrP is necessary for mammary gland development. Our studies have suggested that this molecule participates in the regulation of epithelial-mesenchymal interactions during embryonic mammary development and perhaps also during adolescent ductal morphogenesis. In addition, it has been suggested that PTHrP plays a critical role in the establishment of bone metastases in breast cancer. In this article, we will discuss the current knowledge of the mechanisms underlying PTHrPs actions during normal mammary development and in breast cancer.
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PMID:Parathyroid hormone-related protein: a developmental regulatory molecule necessary for mammary gland development. 1021 4

Breast cancer affects approximately one woman in twelve and kills more women than any other cancer. If detected early, patients have a five year survival rate of 66%, but once metastatic disease has developed, there is no effective treatment. About 70% of patients with metastatic disease have bone involvement, while lungs and liver are the other common targets. Bone metastases cause severe pain, pathological fractures and hypercalcaemia and thus are a significant clinical problem. The development of new therapies for metastatic breast carcinoma depends on a better understanding of the mechanism of homing of the tumour cells to bone, liver and lungs and the factors required for their growth in these organs. Research on mechanisms of breast cancer metastasis, particularly to bone, has relied on in vitro studies or on tumour models in which the inoculation route is designed to promote delivery of tumour cells to a specific organ. Metastases in bone are achieved by inoculation into the right ventricle of the heart. To our knowledge there has been no report of a model of metastatic spread from the mammary gland to distant sites which reliably includes bone. In this paper, we describe our recent development of a novel murine model of metastatic breast carcinoma. The new model is unique in that the pattern of metastatic spread closely resembles that observed in human breast cancer. In particular, these murine breast tumours metastasise to bone from the primary breast site and cause hypercalcaemia, characteristics not normally found in murine tumours, but common in human disease. Furthermore, in a preliminary characterisation of this model, we show that secretion of parathyroid hormone-related protein, a role for which has been implicated in breast cancer spread to bone, correlates with metastasis to bone. This model therefore provides an excellent experimental system in which to investigate the factors that control metastatic spread of breast cancer to specific sites, particularly bone. The special advantage of this system is that it involves the whole metastasis process, beginning from the primary site. Existing models consider mechanisms that pertain to growth of tumour once the site has been reached. An understanding of the regulation of these factors by potential therapeutic agents could lead to improvement in therapies designed to combat metastatic disease. For the first time, this development will allow exploration of the molecular basis of site-specific metastasis of breast cancer to bone in a clinically relevant model.
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PMID:A novel orthotopic model of breast cancer metastasis to bone. 1041 Nov 9

Humoral hypercalcemia of malignancy is a cancer-related hypercalcemia caused by production of humoral factors by malignant cells in patients without bone metastases. Squamous cell carcinomas are the tumors most frequently associated with humoral hypercalcemia of malignancy, and parathyroid hormone-related protein is the main humoral factor implicated. In spite of the fact that normal keratinocytes produce parathyroid hormone-related protein, it is highly unusual for patients with squamous cell carcinomas of the skin to present with humoral hypercalcemia of malignancy. We present a well-documented case of cutaneous squamous cell carcinoma complicated by hypercalcemia in a patient with high levels of plasma parathyroid hormone-related protein and immunohistochemical evidence of high parathyroid hormone-related protein production by the tumoral cells.
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PMID:Immunohistochemical detection of parathyroid hormone-related protein in a cutaneous squamous cell carcinoma causing humoral hypercalcemia of malignancy. 1042 Feb 32

Breast cancers commonly cause osteolytic metastases in bone, a process that is dependent upon osteoclast-mediated bone resorption. Recently the osteoclast differentiation factor (ODF), better termed RANKL (receptor activator of NF-kappaB ligand), expressed by osteoblasts has been cloned as well as its cognate signaling receptor, receptor activator of NFkappaB (RANK), and a secreted decoy receptor osteoprotegerin (OPG) that limits RANKL's biological action. We determined that the breast cancer cell lines MDA-MB-231, MCF-7, and T47D as well as primary breast cancers do not express RANKL but express OPG and RANK. MCF-7, MDA-MB-231, and T47D cells did not act as surrogate osteoblasts to support osteoclast formation in coculture experiments, a result consistent with the fact that they do not express RANKL. When MCF-7 cells overexpressing PTH-related protein (PTHrP) were added to cocultures of murine osteoblasts and hematopoietic cells, osteoclast formation resulted without the addition of any osteotropic agents; cocultures with MCF-7 or MCF-7 cells transfected with pcDNAIneo required exogenous agents for osteoclast formation. When MCF-7 cells overexpressing PTHrP were cultured with murine osteoblasts, osteoblastic RANKL messenger RNA (mRNA) levels were enhanced and osteoblastic OPG mRNA levels diminished; MCF-7 parental cells had no effect on RANKL or OPG mRNA levels when cultured with osteoblastic cells. Using a murine model of breast cancer metastasis to bone, we established that MCF-7 cells that overexpress PTHrP caused significantly more bone metastases, which were associated with increased osteoclast formation, elevated plasma PTHrP concentrations and hypercalcaemia compared with parental or empty vector controls.
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PMID:Breast cancer cells interact with osteoblasts to support osteoclast formation. 1049 98

A 57-year-old woman, with bone, lymph node and skin metastases underwent mastectomy and extirpation of skin tumors. Chemoenderine-therapy was performed from the 15th day after operation, with a toremifene and CEF regimen consisting of cyclophosphamide, epirubicin and 5-fluorouracil. She had nausea and neurological symptoms from hypercalcemia (21.5 mg/dl) on the 28th day after operation. Her serum PTHrP level was found to be high at 214 pmol/l. We administered pamidronate in a dose of 45 mg biweekly, and she improved. The CEF regimen and pamidronate therapy was continued for 6 cycles and the regions of bone metastases were reduced on the bone scintography. Thereafter she has been administered pamidronate 30 mg/4 weeks as an outpatient with no further symptoms, and serum Ca and PTHrP have remained normal. In conclusion, pamidronate combined with chemotherapy can be a therapeutic option for not only hypercalcemia but also bone metastases of breast cancer.
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PMID:[A case of multiple bone metastases from advanced breast cancer effectively treated with pamidronate]. 1050 May 35


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