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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The development and differentiation of the epithelial component of glandular tissues such as the breast is regulated by two apparently unrelated processes. One of these is presumed to be epithelial cell collective autonomous, that is, it is mediated by gene products which act directly on the epithelial cells. An important component of autonomous regulation is the functional expression of homotypic cell-cell adhesion molecules such as cadherins. The second process is non-autonomous and involves an inductive effect of the neighboring mesenchymal cell collective. An important component of non-autonomous regulation is the aggregation/condensation of mesenchyme closely associated with the epithelium. We propose that molecular alterations in autonomous and non-autonomous pathways are important causes and indicators respectively of breast cancer progression and that these two fundamental regulators of epithelial collective organization are in fact inter-dependent. For example, we show that the expression of hepatocyte growth factor (HGF), an epithelially targeted mesenchymally derived morphogenic factor is regulated by mesenchymal cell density (condensation) and by factors released from epithelial cells. Breast epithelial cells produce factors which inhibit and stimulate HGF expression. The inhibitory factor is transforming growth factor beta (TGF-beta) and the activation state of TGF-beta is a crucial element in HGF homeostasis. The balance of negative and positive HGF regulators is markedly affected by the growth conditions and differentiation state of the epithelial cells. The expression of the HGF receptor, met, is high in normal breast epithelial cells and in dedifferentiated (ER negative) tumor cells but is reduced or lost in ER positive well differentiated epithelial cells. Our results indicate that the expression of at least one epithelial morphogen, HGF, is inter-dependently regulated by mesenchymal condensation and by factors released by neighboring epithelial cells.
Breast Cancer Res Treat 1994
PMID:Breast carcinoma: a collective disorder. 753 61

We sought to determine whether the hepatocyte growth factor/scatter factor (HGF/SF)- and keratinocyte growth factor-receptor systems were expressed in normal breast cells, breast carcinoma cell lines, normal breast tissues, and breast cancer tissues. Reverse transcriptase-polymerase chain reaction and hot blotting were used to detect HGF, HGF/SF (met) receptor, KGF, and KGF receptor mRNAs in human mammary epithelial (HME) and stromal (HMS) cells. We also examined breast carcinoma (MDA-MB-157, SCC 38, and SCC 70) and spontaneously immortalized breast epithelial (HMT 3522) cell lines, as well as normal breast and breast carcinoma tissues. PCR products were also confirmed by nucleic acid sequencing. The effects of HGF and KGF, compared to EGF and heparin-binding EGF, on the proliferation of normal human mammary epithelial cells in serum-free defined medium was determined by cell counting. HGF and KGF mRNAs were detected in HMS cells, but not HME cells. KGF receptor mRNA was detected in HME cells, but not HMS cells. HGF/SF receptor mRNA was detected in both HME and HMS cells. mRNAs were also detected in normal breast and breast carcinoma tissues, as well as breast carcinoma and transformed breast epithelial cell lines. Alternative cDNA sequences that are predicted to code for a soluble KGF receptor and a membrane bound, truncated HGF/SF receptor were detected in breast epithelial cells and breast tissues. HGF and KGF maintained viability and stimulated proliferation of HME cells.
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PMID:Hepatocyte growth factor (HGF), keratinocyte growth factor (KGF), and their receptors in human breast cells and tissues: alternative receptors. 786 34

Hepatocyte growth factor/scatter factor (HGF/SF) induces cell motility and tissue remodeling of various epithelial cells through its receptor, the product of the proto-oncogene c-met. High levels of HGF/SF have been correlated with poor prognosis in human breast carcinoma. In this study, we examined the expression of the c-Met receptor in human breast-carcinoma cells in vivo and in cultured cell lines. Immunohistochemical analysis of biopsy samples of human breast carcinoma indicated that, in normal mammary gland, c-Met is localized in the ductal epithelium. The level of expression of c-Met in primary carcinomas was maintained in autologous metastatic lymph-node lesions in some cases, and in other cases was elevated. Frequently there was evidence of heterogeneity in cellular expression of c-Met within individual tumors, suggesting that micro-environmental factors may regulate receptor expression. In an analysis of a panel of human breast-carcinoma cell lines, we found that moderately differentiated cell lines did not express detectable levels of c-Met and were not responsive to HGF. In contrast, poorly differentiated and invasive cell lines did express high levels of the receptor and responded to HGF by increased motility and invasiveness. Sensitivity to HGF/SF also correlated with expression of the c-Met 9-kb mRNA. No correlation was found between gene copy number and the expression level of c-Met protein or mRNA. When the moderately differentiated and c-Met-negative T47D cell line was transfected with c-DNA for c-met, the transfectants showed delayed cell scattering and migratory response to HGF. Thus, over-expression of c-Met in moderately differentiated carcinoma cells may be one of several attributes that contribute to an invasive phenotype during the progression of breast cancer.
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PMID:Expression of the c-Met/HGF receptor in human breast carcinoma: correlation with tumor progression. 922 9

Hepatocyte growth factor/scatter factor (HGF/SF) is a mesenchyme-derived cytokine that stimulates motility and invasiveness of epithelial and cancer cells. These responses are transduced through the c-met proto-oncogene product, a transmembrane tyrosine kinase that functions as the HGF/SF receptor. We have shown that HGF/SF is a potent angiogenic molecule and that its angiogenic activity is mediated primarily through direct actions on vascular endothelial cells. These include stimulation of cell migration, proliferation, protease production, invasion, and organization into capillary-like tubes. We further showed that HGF/SF is overexpressed in invasive human cancers, including breast cancer, relative to non-invasive cancers and benign conditions. In invasive breast cancers, the content of HGF/SF is strongly correlated with that of von Willebrand's factor, a marker of vascular endothelial cells. Furthermore, transfection of breast cancer and glioma cell lines with HGF/SF cDNA greatly enhanced the ability of these cells to grow as tumours in orthotopic sites in syngeneic or immunocompromized host animals. The increased growth rate of the HGF/SF-transfected cells was attributable, in part, to increased tumour angiogenesis. These findings suggest that HGF/SF may function as a tumour progression factor, in part by stimulating tumour cell invasiveness and in part by stimulating angiogenesis.
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PMID:HGF/SF in angiogenesis. 952 73

Scatter factor (SF) (hepatocyte growth factor) is a cytokine that may play a role in human breast cancer invasiveness and angiogenesis. We now report that SF can block the induction of apoptosis by various DNA damaging-agents, including cytotoxic agents used in breast cancer therapy. SF protected MDA-MB-453 human breast cancer cells, EMT6 mouse mammary tumor cells and MDCK renal epithelial cells against apoptosis induced by adriamycin (ADR), X-rays, ultraviolet radiation, and other agents. Protection was observed in assays of DNA fragmentation, cell viability (MTT), and clonogenic survival. Protection of MDA-MB-453 cells against ADR was dose- and time-dependent; maximal protection required pre-incubation with 75-100 ng/ml of SF for 48 h or more. Protection required functional SF receptor (c-Met), but was not dependent on p53. Western blotting analysis revealed that pre-treatment of MDA-MB-453 cells with SF inhibited the ADR-induced decreases in the levels of Bcl-XL, an anti-apoptotic protein related to Bcl-2; and the dose-response and time course characteristics for SF-mediated increases in the Bcl-XL protein levels of ADR-treated cells were consistent with the degrees of protection against apoptosis observed under the same conditions. Furthermore, Bcl-XL levels were not down-regulated by ADR in MDA-MB-231 breast cancer cells, consistent with the finding that SF failed to protect these cells against ADR, despite the fact that they contain functional c-Met receptor. In contrast to Bcl-XL, SF blocked ADR-induced increases in c-Myc and inhibited the expression of p21WAF1/CIP1 and of the BRCA1 protein in MDA-MB-453 cells. However, SF did not cause significant changes in the cell cycle distribution of ADR-treated cells. These findings suggest that SF-mediated protection of human breast cancer cells may involve inhibition of one or more pathways required for the activation of apoptosis and may particularly target the anti-apoptotic mitochondrial membrane pore-forming protein Bcl-XL as a component of the protective mechanism. By implication, the accumulation of SF within human breast cancers may contribute to the development of a radio- or chemoresistant phenotype.
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PMID:Scatter factor protects epithelial and carcinoma cells against apoptosis induced by DNA-damaging agents. 967 97

Hepatocyte growth factor/scatter factor (HGF/SF) is a pluripotent growth factor that exerts mitogenic, motogenic, and morphogenic effects. To elucidate the cellular mechanisms underlying the pluripotent function of this growth factor, T47D human breast cancer cells were transfected with human hgf/sf. The hgf/sf-positive clones exhibited different levels of biologically functional HGF/SF expression and up-regulation of endogenous Met (HGF/SF receptor) expression. In addition, a constitutive phosphorylation of the receptor on tyrosine residues was detected, establishing a Met-HGF/SF autocrine loop. The autocrine activation of Met caused marked inhibition in cell growth accompanied by cell accumulation at G0/G1. These cells underwent terminal cell differentiation as determined by morphological changes, synthesis of milk proteins such as beta-casein and alpha-lactalbumin, and production of lipid vesicles. Our results demonstrate that Met-HGF/SF, an oncogenic signal transduction pathway, is capable of inducing growth arrest and differentiation in certain breast cancer cells and, thus, may have potential as therapeutic and/or prognostic tools in breast cancer treatment.
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PMID:Met-HGF/SF mediates growth arrest and differentiation in T47D breast cancer cells. 1007 6

Tumour cell metastatic potential is significantly enhanced following treatment with HGF/SF, the ligand for the c-met receptor tyrosine kinase. Following c-met activation in tumour cells, phosphorylation of beta-catenin occurs, together with loss of intercellular adhesion and a gain in the motile and invasive nature of the cell. In this study we show that c-met is co-localised with beta-catenin and E-cadherin at regions of cell-cell contact in human colon cancer (HRT18 and HT115) and two breast cancer (MCF7 and MDA MB 231) cell lines. Immunoprecipitation studies demonstrated an association between c-met and members of the cadherin adhesion complex in these epithelial tumour cells, along with the membrane tyrosine protein phophatase, PTPmu. We conclude that the HGF/SF receptor, c-met, together with members of the cadherin/catenin cell-cell adhesion system and PTPmu, may form part of a protein complex in E-cadherin positive tumour cells that acts to regulate intercellular adhesion following HGF/SF stimulation.
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PMID:Association of the HGF/SF receptor, c-met, with the cell-surface adhesion molecule, E-cadherin, and catenins in human tumor cells. 1042 98

Anchorage-independent survival and growth are critical characteristics of malignant cells. We showed previously that the addition of exogenous hepatocyte growth factor (HGF) and the presence of fibronectin fibrils stimulate anchorage-independent colony growth of a murine mammary carcinoma, SP1, which expresses both HGF and HGF receptor (Met; R. Saulnier et al., Exp. Cell Res., 222: 360-369, 1996). We now show that tyrosine phosphorylation of Met in carcinoma cells is augmented by cell adhesion and spreading on fibronectin substratum. In contrast, detached serum-starved cells exhibit reduced tyrosine phosphorylation of Met and undergo apoptotic cell death within 18-24 h. Under these conditions, the addition of HGF stimulates tyrosine phosphorylation of Met and restores survival of carcinoma cells. Soluble fibronectin also stimulates cell survival and shows a cooperative survival response with HGF but does not affect tyrosine phosphorylation of Met; these results indicate that fibronectin acts via a pathway independent of Met in detached cells. We demonstrated previously that inhibition of phosphatidylinositol (PI) 3-kinase activity blocks HGF-induced DNA synthesis of carcinoma cells (N. Rahimi et al., J. Biol. Chem., 271: 24850-24855, 1996). We now show in detached cells a cooperative effect of HGF and FN in the activation of PI 3-kinase and on the phosphorylation of PKB/Akt at serine 473. PI 3-kinase activity is also required for the HGF- and fibronectin-induced survival responses, as well as anchorage-independent colony growth. However, c-Src kinase or MEK1/2 activities are not required for the cell survival effect. Together, these results demonstrate that the PI 3-kinase/Akt pathway is a key effector of the HGF- and fibronectin-induced survival response of breast carcinoma cells under detached conditions and corroborate an interaction between integrin and HGF/ Met signalling pathways in the development of invasive breast cancer.
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PMID:Cooperative effect of hepatocyte growth factor and fibronectin in anchorage-independent survival of mammary carcinoma cells: requirement for phosphatidylinositol 3-kinase activity. 1071 68

NK4 is a variant form of HGF/SF, comprising the N-terminal and subsequent four kringle domains of mature HGF/SF. HGF/SF is a multifunctional cytokine that enhances the metastatic behaviour of tumour cells in vitro by stimulation of the c-met receptor tyrosine kinase and has been implicated in the development of tumour metastasis in vivo. The aims of this study were to further investigate the potential antagonistic effects of the recently described variant form of HGF/SF, NK4, on HGF/SF activity in breast cancer cells. All cell lines used expressed both the HGF/SF receptor gene and protein as shown by RT-PCR and Western blotting. NK4 inhibited HGF/SF-induced tumour cell invasion through an artificial basement membrane. Tumour cell motility and scattering induced by HGF/SF were also dramatically reduced by the inclusion of NK4. Immunoprecipitation studies revealed that NK4 inhibited the phosphorylation of the c-met receptor in response to HGF/SF. Treatment of these cells with NK4 alone did not have any significant effects on their metastatic behaviour. From this data we conclude that NK4 demonstrates significant antagonistic properties towards HGF/SF, inhibiting HGF/SF-stimulated breast tumour cell invasion, motility and migration. NK4 may therefore be of potential benefit in the development of anti-metastasis therapies.
Breast Cancer Res Treat 2000 Feb
PMID:Inhibition of HGF/SF-induced breast cancer cell motility and invasion by the HGF/SF variant, NK4. 1083 94

Matriptase is an epithelial-derived, integral membrane serine protease. The enzyme was initially isolated from human breast cancer cells and has been implicated in breast cancer invasion and metastasis. In the current study, using active matriptase isolated from human milk, we demonstrate that matriptase is able to cleave various synthetic substrates with arginine or lysine as their P1 sites and prefers small side chain amino acids, such as Ala and Gly, at P2 sites. For the most reactive substrates, N-tert-butoxycarbonyl (N-t-Boc)-gamma-benzyl-Glu-Ala-Arg-7-amino-4-methylcoumarin (AMC) and N-t-Boc-Gln-Ala-Arg-AMC, the K(m) values were determined to be 3. 81 and 4.89 microm, respectively. We further demonstrated that matriptase can convert hepatocyte growth factor/scattering factor to its active form, which can induce scatter of Madin-Darby canine kidney epithelial cells and can activate c-Met tyrosine phosphorylation in A549 human lung carcinoma cells. In addition, we noted that matriptase can activate urokinase plasminogen activator but has no affect on plasminogen. These results suggest that matriptase could act as an epithelial, upstream membrane activator to recruit and activate stromal-derived downstream effectors important for extracellular matrix degradation and epithelial migration, two major events of tissue remodeling, cancer invasion, and metastasis.
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PMID:Activation of hepatocyte growth factor and urokinase/plasminogen activator by matriptase, an epithelial membrane serine protease. 1096 9


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