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Query: UMLS:C0278488 (metastatic breast cancer)
 7,812 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

New human breast cell lines were developed from metastatic breast cancer tissues and normal breast tissues. Primary cultures were initiated from cellular outgrowths of explanted tissues or from mechanically isolated cells in two serum-free media. Cell cultures derived from both cancer and normal tissues were immortalized with pRSV-T plasmid to generate permanent breast cell lines that exhibited an epithelial morphology. Cell lines generated in this study were characterized with respect to morphology, growth rate, karyotype, presence of specific genes, and the expression of epithelial and breast markers. The cell lines expressed the epithelial cell markers, cytokeratins 8 and 18, and retained the capacity to produce human milk fat globulin. They also express the BRCA-1, erbB2, and EGF receptor genes and possess the H-ras, K-ras, and p53 genes. Preliminary data showed that one of the new cancer cell lines was highly sensitive to the cytotoxic action of taxol. It is envisioned that the new breast cell lines will be useful as targets for identification of therapeutic agents against breast cancer and as models for carcinogenesis studies.
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PMID:Development and characterization of new immortalized human breast cell lines 961 44

The search for new methods of treating cancer, combined with advances in our understanding of carcinogenesis, molecular biology and technology, has resulted in the development of novel biologic agents with proven clinical efficacy. One such agent is trastuzumab (Herceptin), a humanized monoclonal antibody that targets the human epidermal growth factor receptor-2 (HER2). HER2 is a member of a family of receptors that interact with each other and various ligands to stimulate various intracellular signal transduction pathways involved in cell growth control. HER2 is overexpressed in 20%-30% of women with breast cancer and is associated with aggressive tumor characteristics and poor prognosis. Trastuzumab is the first humanized monoclonal antibody to be approved for therapeutic use and the first oncogene-targeted treatment with proven survival benefit in women with HER2-positive metastatic breast cancer. However, its mechanism of action has not been fully characterized and appears to be complex. This paper reviews current knowledge of the mechanism of action of trastuzumab, including HER2 protein downregulation, prevention of HER2-containing heterodimer formation, initiation of G1 arrest and induction of p27, prevention of HER2 cleavage, inhibition of angiogenesis, and induction of immune mechanisms. The significance of these mechanisms for selection of concomitant chemotherapy is also considered.
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PMID:Mechanism of action of anti-HER2 monoclonal antibodies. 1152 20

Overexpression of the Erb B-2 receptor plays an important role in the pathogenesis of breast cancer. It results in the formation of heterodimers consisting of Erb-B2/Erb B-3 receptors which have an ability to produce stable and external factors independent mitotic stimuli. Together with an autocrine stimulation of neoplastic cell proliferation by heregulin and cyclooxygenase 2 activation it is a significant factor in carcinogenesis. Overexpression of Erb B-2 seems to be an independent negative prognostic factor in breast cancer. Its predictive value is not clear-cut. It is suggested that breast cancer showing Erb B-2 overexpression is more sensitive to treatment with anthracyclines and less to CMF. The anti-Erb B-2 monoclonal antibody (trastuzumab) is used in treatment of metastatic breast cancer both as a single drug and in combination with chemotherapy.
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PMID:[Erb-2 overexpression in breast cancer]. 1291 78

The tumor biology of the individual patients' disease is increasingly becoming an important factor to consider when choosing a treatment for breast cancer. Equally, there is now more emphasis on understanding the mechanisms of carcinogenesis and how these can be exploited when designing new therapeutic agents. Tumorigenesis in humans is a multistep process involving genetic alterations that drive the progressive transformation of normal cells into malignant types. Dysregulated processes involved in tumorigenesis, such as regulation of cell cycle progression, angiogenesis, and apoptosis provide rational targets for novel therapies. The family of human epidermal growth factor receptors (HER) is well characterized and its role in normal cell growth and tumorigenesis has been extensively researched. Trastuzumab (Herceptin; F. Hoffmann-La Roche, Basel, Switzerland), an anti-HER2 monoclonal antibody (MAb), was one of the first rationally developed and clinically available targeted agents, setting the precedent for providing specific therapy for HER-dysregulated cancer. This and other targeted agents show how research in tumor biology can be used to develop improved cancer therapies. Capecitabine (Xeloda; F. Hoffmann-La Roche) is an example of a rationally designed cytotoxic treatment. It is designed to generate 5-fluorouracil preferentially in tumor cells by exploiting the higher activity of the activating enzyme thymidine phosphorylase in tumors compared with healthy tissues. Tumor-specific activation has the potential to enhance efficacy and minimize toxicity. Proof of this principle is provided by clinical trial results showing that capecitabine is effective and has a favorable safety profile in the treatment of metastatic breast cancer. In summary, we are now at the stage where breast cancer treatment will be determined by tumor biology as well as patient characteristics. Improved molecular characterization and greater understanding of tumorigenesis will enable more individualized treatment.
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PMID:Molecular approach to breast cancer treatment. 1549 Mar 69

Expression of urokinase-type plasminogen activator (uPA), a protease only expressed in highly invasive human breast cancer cells, is inhibited by DNA methylation of its promoter. We tested the hypothesis that up-regulation of DNA methyltransferase 1 (DNMT1) will lead to methylation and silencing of uPA and inhibition of the invasiveness of metastatic breast cancer cells. Since RAS was previously shown to up-regulate DNA methylation, we examined the effects of ectopic expression of constitutively active RAS on methylation and expression of uPA. Transfection of Ha-RAS into MDA-MB-231 human breast cancer cells resulted in a significantly shorter cell doubling time compared with the controls. However, expression and activity of the metastatic gene uPA and invasive capacity of the cells were significantly reduced by the oncogene RAS. Silencing of uPA by RAS is mediated by a cis modification of the uPA promoter and not through an effect on a trans-acting factor, since a transiently transfected unmethylated uPA-luicferase reporter is expressed at a similar level in RAS-transfected and control cells. We then examined the levels of DNMT1 and methylated DNA-binding protein 2 (MBD2) expressions in these cells to determine whether this reduction in uPA expression is associated with changes in the DNA methylation machinery. Our results showed that ectopic expression of RAS induced DNMT1 expression and activity and inhibited MBD2 expression. Consistent with methylation-mediated repression, uPA was partially methylated in RAS-transfected cells and uPA expression was induced upon treatment of RAS transfectants with the demethylating agent 5'-azacytidine. These results therefore imply that the RAS-DNMT1 DNA methylation pathway which promotes oncogenic growth in many cancers can exert an opposite effect on the invasive capacity of the highly invasive MDA-MB-231 cells, thus illustrating the divergence of growth and metastasis promoting pathways in cancer. This has important implications for new therapeutic approaches to metastasizing cancer.
Carcinogenesis 2005 Mar
PMID:Methylation and inhibition of expression of uPA by the RAS oncogene: divergence of growth control and invasion in breast cancer cells. 1561 32

Breast cancer most frequently metastasizes to bone causing decreased quality of life and morbidity. Since current treatments are palliative, strategies to prevent bone metastases in breast cancer patients are required. There is substantial evidence indicating that high levels of nitric oxide (NO) suppress tumor growth and metastasis in vivo. We hypothesize that agents that produce high concentrations of NO could prevent the spread of breast cancer to bone. We previously demonstrated that the synthetic retinoid N-(4-hydroxyphenyl)retinamide (4-HPR) produces high levels of NO via the induction of NO synthases. NO pro-drugs are designed to produce large amounts of NO without inducing NO synthases but upon metabolism by their intracellular targets. The objective of this study was to determine the effectiveness of 4-HPR and an NO pro-drug, diethylamineNONOate/AM (NONO-AM), in inhibiting the growth and invasiveness of bone metastatic breast cancer cells. Parental MDA-MB-231 breast cancer cells were resistant to 4-HPR-induced apoptosis at clinically relevant doses, whereas 4-HPR-induced apoptosis in a dose-dependent manner in MDA-MB-231/F10 bone metastatic breast cancer cells. Unlike 4-HPR, NONO-AM induced apoptosis in a dose-dependent manner in both parental MDA-MB-231 cells and F10 cells. The bone metastatic F10 cells were more sensitive to the anti-invasive effects of 4-HPR and NONO-AM than were MDA-MB-231 cells. Although suppression of matrix metalloprotease-9 activity may be one mechanism by which 4-HPR decreases the invasion of F10 cells, it does not appear to be the anti-invasion mechanism of NONO-AM. These in vitro results suggest that 4-HPR and NO pro-drugs may be effective chemopreventive agents against bone metastatic breast cancer.
Carcinogenesis 2006 Mar
PMID:N-(4-Hydroxyphenyl)retinamide and nitric oxide pro-drugs exhibit apoptotic and anti-invasive effects against bone metastatic breast cancer cells. 1619 39

The strategies available for the treatment of metastatic breast cancer are limited. Dietary botanicals may have a better protective effect on this disease. We therefore investigated the effects of grape seed proanthocyanidins (GSPs) on a highly metastatic mouse mammary carcinoma cell line. In vitro treatment of breast cancer cells, 4T1, MCF-7 and MDA-MB-468, with GSPs resulted in significant inhibition of cellular proliferation and viability, and induction of apoptosis in 4T1 cells in a time- and dose-dependent manner. Further analysis indicated an alteration in the ratio of Bax/Bcl-2 proteins in favor of apoptosis, and the knockdown of Bax using Bax siRNA transfection of 4T1 cells resulted in blocking of GSPs-induced apoptosis. Induction of apoptosis was associated with the release of cytochrome c, increased expression of Apaf-1 and activation of caspase 3 and poly (ADP-ribose) polymerase. Treatment with the pan-caspase inhibitor (Z-VAD-FMK) resulted in partial but significant inhibition of apoptosis in 4T1 cells suggesting the involvement of both caspase activation-dependent and activation-independent pathways in the apoptosis of 4T1 cells induced by GSPs. The effects of dietary GSPs were then examined using an in vivo model in which 4T1 cells were implanted subcutaneously in Balb/c mice. Dietary GSPs (0.2 and 0.5%, w/w) significantly inhibited the growth of the implanted 4T1 tumor cells and increased the ratio of Bax:Bcl-2 proteins, cytochrome c release, induction of Apaf-1 and activation of caspase 3 in the tumor microenvironment. Notably, the metastasis of tumor cells to the lungs was inhibited significantly and the survival of the mice enhanced. These data suggest that GSPs possess chemotherapeutic efficacy against breast cancer including inhibition of metastasis.
Carcinogenesis 2006 Aug
PMID:Grape seed proanthocyanidins induce apoptosis and inhibit metastasis of highly metastatic breast carcinoma cells. 1659 45

The carcinogenesis process is characterized, in part, by the dysfunction of cellular communication pathways, such as the one involving HER2. HER2 is a member of the EGF receptor family, which participates in cell growth and proliferation. HER2 may be overexpressed in 15 to 30% of breast cancer cases and is associated with poor prognosis, shortened overall survival and shorter time to disease progression. Furthermore, an increasing number of studies have demonstrated the relevance of HER2 serum concentrations (sHER2, extracellular domain released into blood by proteolysis) as a predictive marker of resistance to chemotherapy in HER2-overexpressing metastatic breast cancer. The determination of HER2 overexpression/ amplification in the diagnosis of relapse of breast cancer is currently a routine procedure. Immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) techniques, which are used to detect HER2 expression in the tumor, are improving constantly, and other parallel techniques such as chromogenic in situ hybridization (CISH) are starting to emerge. sHER2 concentrations can be measured using ELISA techniques, which can be automated. All of these procedures still need to be standardized. The discovery of a monoclonal antibody (4D5) that can inhibit the growth and proliferation of cells overexpressing HER2 led to the development of trastuzumab. Like 4D5, trastuzumab recognizes an epitope on the extracellular domain of HER2. Moreover, trastuzumab is also able to stimulate antibody-dependent cellular toxicity (ADCC). It is administered alone or in combination (with navelbine, taxol, carboplatin...) in patients with metastatic breast cancer overexpressing HER2. Other active antibodies have since been discovered, as well as other specific molecules, such as tyrosine kinase inhibitors which will undoubtedly find a place in the therapeutic arsenal used in breast cancer, especially to avoid the emergence of resistance to treatment.
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PMID:Prospect for anti-HER2 receptor therapy in breast cancer. 1673 6

Transforming growth factor betas (TGF-beta) play a dual role in carcinogenesis, functioning as tumor suppressors early in the process, and then switching to act as prometastatic factors in late-stage disease. We have previously shown that high molecular weight TGF-beta antagonists can suppress metastasis without the predicted toxicities. To address the underlying mechanisms, we have used the 4T1 syngeneic mouse model of metastatic breast cancer. Treatment of mice with a monoclonal anti-TGF-beta antibody (1D11) significantly suppressed metastasis of 4T1 cells to the lungs. When metastatic 4T1 cells were recovered from lungs of 1D11-treated and control mice, the most differentially expressed gene was found to be bone sialoprotein (Bsp). Immunostaining confirmed the loss of Bsp protein in 1D11-treated lung metastases, and TGF-beta was shown to regulate and correlate with Bsp expression in vitro. Functionally, knockdown of Bsp in 4T1 cells reduced the ability of TGF-beta to induce local collagen degradation and invasion in vitro, and treatment with recombinant Bsp protected 4T1 cells from complement-mediated lysis. Finally, suppression of Bsp in 4T1 cells reduced metastasis in vivo. We conclude that Bsp is a plausible mediator of at least some of the tumor cell-targeted prometastatic activity of TGF-beta in this model and that Bsp expression in metastases can be successfully suppressed by systemic treatment with anti-TGF-beta antibodies.
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PMID:Bone sialoprotein mediates the tumor cell-targeted prometastatic activity of transforming growth factor beta in a mouse model of breast cancer. 1677 10

CXCR4 is a chemokine receptor probably involved in the homing of metastatic breast cancer, and its expression is modulated by tumor environmental stimuli such as hepatocyte growth factor (HGF) and hypoxia. Here, we demonstrate that, depending on the stimulus, different transcription factors can cooperate in enhancing CXCR4 transcription in MCF-7 breast cancer cell line. In HGF-treated MCF-7 cells, the DNA binding of Ets1 activated by MAPK1/ERK1/2 transduction pathway as well as the DNA binding of NF-kappaB played a critical role in CXCR4 transcription and protein induction. Under HGF stimulation, the blockade of these transcription factors by dominant negatives and inhibitors prevented the expression of CXCR4 receptor, the activity of a gene reporter driven by CXCR4 promoter sequence and the chemoinvasion toward the CXCL12 ligand. NF-kappaB was activated also by hypoxia and contributed, with HIF-1, to the increase in CXCR4 expression. The results suggest that Ets1, specifically activated by HGF, might cooperate with NF-kappaB activity to enhance the invasive/metastatic phenotype of breast carcinoma cells.
Carcinogenesis 2007 Feb
PMID:HGF induces CXCR4 and CXCL12-mediated tumor invasion through Ets1 and NF-kappaB. 1684 Apr 40


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