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

Endocrine therapy is one of the principal treatment modalities of breast cancer, both in an adjuvant setting and in advanced disease. The T61 breast cancer xenograft described here provides an experimental model of the effects of estrogen treatment at a molecular level. T61 is an estrogen receptor positive tumor which was originally derived from a T1N0M0 invasive ductal cancer and has been carried as a serially transplanted xenograft in nude mice. T61 is a hormone sensitive tumor whose growth is suppressed by both estrogen and tamoxifen, in contrast to other estrogen receptor positive tumors such as MCF-7 which are stimulated by estrogen. Molecular studies have demonstrated that T61 expresses easily detectable levels of mRNA for a number of peptide growth factors, including transforming growth factor alpha (TGF-alpha) and insulin-like growth factors I and II (IGF-I and IGF-II), but not transforming growth factor beta-I (TGF-beta1). Of these, IGF-II is the only peptide whose expression is altered by endocrine therapy. Treatment of T61-bearing nude mice with physiologic doses of estrogen is accompanied by loss of IGF-II mRNA expression within 24 hours, and rapid regression of tumor. T61 tumor growth is also inhibited in animals treated with a monoclonal antibody which blocks binding of ligand to the IGF-I receptor, which mediates the mitogenic signal of bound IGF-II through autophosphorylation of its intracellular tyrosine kinase domain. These results demonstrate the utility of the T61 model in the study of the molecular mechanism of estrogen therapy in breast cancer, and suggest that in this system, modulation of a specific growth factor (IGF-II) by endocrine therapy can have profound effects on tumor growth.
Breast Cancer Res Treat 1996
PMID:The T61 human breast cancer xenograft: an experimental model of estrogen therapy of breast cancer. 873 8

1. Signal transduction pathways activated during growth of human breast cancer cells in tissue culture are reviewed. 2. Steroid hormones and growth factors stimulate similar mitogenic pathways and frequently modulate each other's activity. 3. A response common to estrogen, progestins and most polypeptide mitogens is induction of the nuclear transcription factors myc, fos and jun in early G1 phase of the cell cycle. 4. Some growth factors also stimulate cyclin D1, a regulatory protein responsible for the activation of cell cycle-dependent kinases in G1. 5. In addition, insulin, IGF-I and EGF activate tyrosine kinase receptors. 6. Several tyrosine phosphorylated proteins occur in human breast cancer cells, and include the EGF and estrogen receptors. 7. Cyclic AMP plays a critical role in breast cancer cell proliferation through the activation of protein kinase A, and it also modulates the activity of estrogen and progesterone receptors. 8. EGF is the only breast cell mitogen known to raise intracellular free calcium levels. 9. Calcium may play a dual role in breast cancer cell proliferation, activating both calmodulin-dependent processes and regulating cell membrane potential through the activation of potassium channels. 10. Potassium channel activity and cell proliferation are linked in breast cancer cells, the cell membrane potential shifting between a depolarized state in G1/G0 cells and a hyperpolarized state during S phase. 11. Activation of an ATP-sensitive potassium channel is required for breast cancer cells to undergo the G1/G0-S transition.
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PMID:Mitogenic signal transduction in human breast cancer cells. 874 51

The adhesion of cancer cells to the vascular endothelium is an important step in the hematogenous metastasis of cancer. Human breast cancer cells adhere to human umbilical vein endothelial cells (HUVECs) through the interaction of E selection on HUVECs and the carbohydrate ligand sialyl Lewisx on the cancer cells. We investigated the alteration of integrin expression on human breast cancer cells, following selectin-mediated initial adhesion to HUVECs. Four cell lines derived from human breast cancer expressed alpha 2-, alpha 3-, alpha 5-, alpha 6- and beta 1-integrins. The expression of alpha 2 beta 1- and alpha 3 beta 1-integrins on BT-20 cells, strongly expressing epidermal growth factor (EGF) receptors, was markedly increased by addition of the heparin-binding EGF-like growth factor (HB-EGF). The expression of alpha 2 beta 1-integrin on SK-BR-3 cells also was increased by the addition of HB-EGF. However, no such effect of HB-EGF on the expression of integrins was observed in T-47D and MCF-7 cells, nor on expression of the EGF receptor. The increase of integrin expression in BT-20 cells was inhibited by the addition of the tyrosine kinase inhibitor genistein. HB-EGF treatment of BT-20 or SK-BR-3 cells resulted in the augmentation of cancer cell adhesion to immobilized collagen. When BT-20 cells were cocultured with HUVECs, a similar level of augmentation of cancer cell adhesion to collagen was observed. The augmentation of cancer cell adhesion to collagen was inhibited by addition of an anti-HB-EGF-neutralizing antibody. Our interpretation of the results described above is that the cancer cells receive stimulation from cytokines, such as HB-EGF, produced by vascular endothelial cells, following the initial adhesion of cancer cells via selectins. This results in a secondary increase in the expression of cell adhesion molecules, such as the beta 1-integrin family, and leads to augmentation in the adhesive activities of cancer cells at the vessel walls. We postulate that these events are the ones involved in the enhanced transmigration of cancer cells to extravascular tissues following the selectin-mediated adhesion to the endothelium.
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PMID:Alteration of integrins by heparin-binding EGF-like growth factor in human breast cancer cells. 878 71

Interleukins-1 (IL-1s) are known to inhibit the growth of cultured breast cancer cells. We examined the effects of IL-1 alpha and IL-1 beta on insulin and insulin-like growth factor I (IGF-I) stimulation of cell growth and found that both IL-1s inhibited anchorage-dependent and independent growth of MCF-7 breast cancer cells. In cells incubated with IL-1 beta (100 U/ml), insulin receptor (IR) protein and messenger RNA were increased by 100%, while IGF-I receptor protein and transcript were not significantly changed. These data were confirmed by binding studies. Incubation of MCF-7 cells with IL-1s led, however, to a significant inhibition of IR and IGF-I receptor autophosphorylation (-55%) and phosphotransferase activity (-65%). Also, in 3T3/ HIR rat fibroblasts, transfected with and overexpressing IR, IL-1s decreased insulin-stimulated cell growth in soft agar and IR tyrosine kinase activity. The present findings suggest that IL-1s antagonize the insulin and IGF-I mitogenic effects in MCF-7 cells by blocking the receptor tyrosine kinase activity that is crucial for the mitogenic effect of these factors.
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PMID:Interleukin-1 blocks insulin and insulin-like growth factor-stimulated growth in MCF-7 human breast cancer cells by inhibiting receptor tyrosine kinase activity. 882 63

EGF receptor (EGF-R) and c-erbB-2 are homologous tyrosine kinase transmembrane receptors. They are involved in controlling proliferation, and probably differentiation, of normal breast epithelial cells, and their expression has been linked to the prognosis of breast cancer. Their physiological roles in normal breast tissue remain to be elucidated, as most studies to date have involved breast cancer cell lines. We studied the location of EGF-R and c-erbB-2 in 100 samples of normal breast with standard immunohistochemical methods and double-labelling techniques. EGF-R was mainly expressed on the stroma and myoepithelial cells, whereas c-erbB-2 expression was exclusively epithelial. An image analyser was used to quantitate variations in their expression during the menstrual cycle. EGF-R and c-erbB-2 expression on epithelial cells was stronger during the luteal phase than the follicular phase (p < 0.01 for EGF-R). The pattern of expression was also compared with that in 28 breast cancers and 7 fibroadenomas.
Breast Cancer Res Treat 1996
PMID:Epidermal growth factor receptor and c-erbB-2 expression in normal breast tissue during the menstrual cycle. 886 41

An enzyme-linked immunosorbent assay is described for the determination of protein tyrosine kinase activity originating from the presence of src-like tyrosine kinases in biological samples. In this assay a peptide derived from p34cdc2, cdc2(6-20)NH2, is coupled to the wells of a maleic anhydride-activated microtiter plate. This particular peptide has been described as an efficient and specific substrate for protein tyrosine kinases belonging to the src family kinases (Cheng et al., J.Biol.Chem. 267 (1992) 9248-9256). After incubation of the coated substrate with sample and ATP, the amount of phosphorylated tyrosyl residues is determined with phosphotyrosine specific antibodies and a secondary peroxidase-labeled antibody. The assay appears to be very sensitive and is linear with sample protein concentration and phosphorylation time. Intra-assay variation is < 5%, whereas day-to-day variation is < 10%. The results of the assay have been compared with an ELISA in which the broad-specificity tyrosine kinase substrate poly(GluNa,Tyr)4:1 was coated. The results of both assays in 27 cytosolic breast cancer samples correlated very well (r = 0.94), in accordance with the predominant expression of src kinase activity in breast cancers (Ottenhoff-Kalff et al., Cancer Res. 52 (1992), 4773-4778). The present assay provides an easy, reproducible, and quick alternative for the usual radioactive methods used for the determination of src-kinase activities including immunecomplex kinase assay and TCA-precipitation assays. It allows the determination of src-like activities in human tumors for routine diagnostic purposes.
Breast Cancer Res Treat 1996
PMID:An enzyme-linked immunosorbent assay for the determination of src-family tyrosine kinase activity in breast cancer. 887 22

The polypeptide hormone prolactin (Prl), acting through its cell surface receptors, promotes growth and differentiation in normal and malignant breast cells. We demonstrate herein that two Prl-responsive cell lines, NOG-8 normal mouse mammary epithelial and T47D human breast cancer cells, respond to Prl by rapid and transient activation of a series of kinases. Raf-1 was activated within 2-5 min of Prl treatment. This was followed rapidly by activation of MEK (MAP kinase kinase) and MAP kinase activity in these cells. Increased MAP kinase activity was accompanied by tyrosine phosphorylation of both the 42 kDa and 44 kDa isoforms. The tyrosine kinase inhibitors genestein and tyrphostin blocked the increase in MAP kinase activity as well as Prl induced growth of the T47D cells. These results indicate that the Prl receptor, after binding to Prl in mammary cells, activates the raf-MEK-MAP kinase pathway for signal transduction leading to mitogenesis.
Breast Cancer Res Treat 1996
PMID:Activation of raf-1, MEK, and MAP kinase in prolactin responsive mammary cells. 887 80

Genistein is a naturally occurring dietary protein tyrosine kinase (PTK) inhibitor that is hypothesized to be responsible for the lower rate of breast cancer observed in Asian women consuming soy. Although genistein is a potent in vitro PTK inhibitor, its mechanism of action in vivo is not known. In vivo, breast cancer growth is regulated by estrogens and peptide growth factors, such as epidermal growth factor (EGF), the receptor of which has intrinsic PTK activity. Therefore, genistein may block mammary epithelial cell growth by interfering with signal transduction events stimulated by estradiol or growth factors. The effect of genistein, related isoflavones, and other tyrosine kinase inhibitors on fetal bovine serum-, estradiol-, and EGF-stimulated cell growth and signal transduction pathways was examined in five human breast cancer cell lines. Genistein inhibited the growth of these cells by each of the growth stimuli with IC50 values ranging from 2.6 to over 20 micrograms/ml. Growth inhibition by genistein was cytostatic and reversible at IC50 concentrations. Related isoflavones were less potent growth inhibitors than genistein, whereas the synthetic PTK inhibitor tyrphostin A25 was an equally potent growth inhibitor. The mechanism of genistein growth inhibition in human breast cancer cells did not depend on the presence of functional estrogen receptor signaling pathways or on inhibition of EGF-receptor PTK activity. Furthermore, genistein (< or = 20 micrograms/ml) did not decrease constitutive or EGF-induced tyrosine phosphorylation as determined by Western blotting with antiphosphotyrosine antibodies. These data suggest that although genistein inhibits the growth of breast cancer cells in culture, it does so without gross inhibition of PTK activity.
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PMID:Genistein inhibits both estrogen and growth factor-stimulated proliferation of human breast cancer cells. 889 38

Tyrosine kinase dependent oncogenes and growth factor receptors are of prognostic importance in breast cancer, but the relation of cytosolic protein tyrosine kinase (PTK) activity to traditional prognostic indicators is poorly defined. We determined cytosolic PTK activity in tumor extracts of 61 women with invasive breast cancer, including 51 primary specimens and 12 nodal or metastatic specimens, 7 women with in situ breast cancer, and 8 control breast specimens. PTK activity (pmol/min/mg) was measured in a dot blot assay using phosphotyrosine antibodies to detect phosphorylated tyrosyl residues in the tissue extracts. Compared with control specimens (mean PTK = 20.5), tyrosine kinase activity was significantly greater in invasive primary cancers (mean PTK = 298.1; p = 0.0008), and nodal/metastatic specimens (mean PTK = 491.5; p = 0.0009). PTK levels of invasive cancers did not correlate with age (p = 0.36), tumor size (p = 0.83), nodal status (p = 0.37), estrogen receptor status (p = 0.66), or progesterone receptor status (p = 0.09). Thus, while tyrosine kinase activity is increased in breast cancer, correlations with traditional prognostic indicators were not found.
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PMID:Protein tyrosine kinase activity in breast cancer and its relation to prognostic indicators. 892 Jul 63

MDA-MB231 human breast cancer cells are unresponsive to insulin and contain a glycoprotein inhibitor of insulin-stimulated insulin receptor (IR) tyrosine kinase activity. Prior studies in both fibroblasts from insulin- resistant non-insulin-dependent diabetes mellitus patients and transfected cells indicate that overexpression of membrane glycoprotein PC-1 reduces IR tyrosine kinase activity. In the present study, we measured PC-1 content and activity in MDA-MB231 and four other human breast cancer cell lines. We observed that PC-1 expression was 3- to 30-fold higher in MDA-MB231 cells when compared with the other breast cell lines. Wheat germ agglutinin extracts of MDA-MB231 cells inhibited IR tyrosine kinase activity. Treatment of these extracts with an antibody to PC-1 significantly reduced their ability to inhibit insulin-stimulated IR tyrosine kinase activity. In addition, when cell clones with different PC-1 activity were selected from MDA-MB231 cells, we found an inverse correlation (r = -0.741, P = 0.006) between the PC-1 activity and the insulin-stimulated IR autophosphorylation. A similar inverse correlation was observed in cell clones derived from the insulin-responsive breast cancer cell line MCF-7. By both immunoprecipitation and cross-linking studies we found PC-1 to be associated with IR. These studies indicate, therefore, that overexpression of PC-1 in MDA-MB231 cells may account, at least in part, for the reduced IR tyrosine kinase activity and suggest that PC-1 is a specific modulator of the IR activity in breast cancer cells.
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PMID:Overexpression of membrane glycoprotein PC-1 in MDA-MB231 breast cancer cells is associated with inhibition of insulin receptor tyrosine kinase activity. 892 58


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