Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Various investigators have shown that the IGFs are mitogens for breast cancer cells. The expression of the IGF receptors is seen in most breast cancer cell lines and tissues, suggesting that most breast cancers have the ability to respond to the IGFs. Although authentic IGF-I is not expressed by breast cancer cell lines, it is possible that an IGF-related peptide that can be detected immunologically is expressed. Furthermore, in estrogen responsive xenotransplants, changes in the level of IGF-II mRNA correlate directly with estrogen-mediated changes in tumor growth. These observations suggest that IGF-II may be important in tumorigenesis and may serve as an autocrine growth stimulator of breast cancer cells. When human breast cancer tissues are studied, IGF-I and IGF-II mRNA expression are commonly seen. However, in situ hybridization studies suggest that IGF-I mRNA is expressed mainly by the stromal elements, while IGF-II mRNA can be found both in stroma and malignant epithelial cells. These observations support the studies done with breast cancer cell lines; IGF-I may stimulate cells via a paracrine pathway, while IGF-II may act as both an autocrine and paracrine growth factor. In addition, IGF-BPs are commonly expressed by breast cancer cells in culture, and it is possible that expression of the IGF-BPs act to modulate the effects of either IGF-I or IGF-II. We propose that the IGFs are important stimulators of breast cancer cells and that their growth promoting effects may be mediated by autocrine, paracrine, or endocrine mechanisms. Furthermore, interactions between the stroma and malignant epithelial cells may be important in regulating the growth of breast cancer. The biological importance of a fibroblast-epithelial cell interaction has been demonstrated in a normal mouse mammary cell line; morphological and functional changes in epithelial cells were induced when the cells were in direct contact with fibroblasts. Similar mechanisms may be important in malignant breast epithelial cells. For example, many breast cancer cells produce platelet-derived growth factor (PDGF) yet have no PDGF receptor. PDGF has been demonstrated to increase IGF-I production by fibroblasts, and a dual paracrine pathway involving PDGF and IGF-I expression by epithelial cells and stromal cells could be envisioned. The pathways through which the IGF system may function in human breast cancer are schematically represented in figure 1. Further work in our laboratory is directed at clarifying the role for the IGFs in breast cancer growth.
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PMID:The insulin-like growth factors, their receptors, and their binding proteins in human breast cancer. 167 92

Human breast cancer cells (HBCC) secrete at least four different forms of IGFBPs. We have previously demonstrated that hIGFBP-1 is a minor component of IGFBPs secreted by Hs578T cells and is absent in CM from MCF-7 cells. In our present report, we describe the immunological and structural relationship of HBCC IGFBPs to hIGFBP-2 and hIGFBP-3. Analysis of conditioned media (CM) from Hs578T by Western ligand blotting revealed three IGFBPs of apparent Mr = 38K, 28K, and 24K; CM from MCF-7 revealed only two IGFBPs, of apparent Mr = 31K and 24K. Immunoprecipitation studies with polyclonal antibodies raised against hIGFBP-2 and hIGFBP-3 demonstrated that the 38K IGFBP in Hs578T CM is immunologically related to hIGFBP-3, while the 31K IGFBP in MCF-7 cells is related to the hIGFBP-2. Analysis by Northern blot demonstrated that MCF-7 cells contained mRNA for hIGFBP-2, while Hs578T cells contained the mRNA characteristic of the hIGFBP-3. The identity of the 24K IGFBP remains unknown, and may represent a distinct IGFBP. Of note, assay of CM following removal of BPs by acid chromatography demonstrated no detectable IGF-I or -II. The role of these IGFBPs in HBCC is of interest in view of the potential modulation of IGF actions by these proteins.
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PMID:Insulin-like growth factor binding proteins in human breast cancer cells: relationship to hIGFBP-2 and hIGFBP-3. 169 78

In this study, the polyanionic compound suramin was shown to be a potent in vitro growth inhibitor of both hormone-insensitive, estrogen receptor-negative human breast cancer cells (MDA MB231 and SK-BR-3) and hormone-responsive, estrogen receptor-positive human breast cancer cells (ZR 75-1, T47D, and MCF7). The inhibitory effect of suramin was dose dependent, with a median effective dose varying from 7 microM for MDA MB231 cells to 50 microM for MCF7 cells. This result indicated that estrogen receptor-negative cells were more sensitive to the drug. In MCF7 cells, not only did suramin block the mitogenic action of growth factors such as epidermal growth factor (EGF) and insulin-like growth factors I and II (IGF-I and IGF-II, respectively), but it also totally abolished the increase in cell proliferation induced by the steroid hormone 17 beta-estradiol (E2). Maximal inhibition was obtained after 5 days of suramin treatment, and inhibition either was partially reversed by E2, IGF-I, and IGF-II or was not reversible by EGF following removal of drug. In addition, suramin significantly decreased synthesis and secretion of the lysosomal enzyme cathepsin D, which was shown to be associated with a high risk of breast tumor metastasis. These results therefore suggest that, because of its effects on growth and cathepsin D secretion, suramin might be a helpful additional therapeutic tool for breast cancer patients, especially for patients with estrogen receptor-negative tumors which are insensitive to antihormonal strategies.
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PMID:Inhibition of breast cancer growth by suramin. 173 71

The effects of estrogens and tamoxifen were analyzed on estrogen receptor-positive human breast cancer (MCF-7) transplanted into athymic nude mice. It was found that (1) the tumor growth and the proportion of 3H-thymidine-labeled cells were significantly increased in the 17 beta-estradiol dipropionate (E2) group, but significantly decreased in the tamoxifen (TAM) group with respect to the control group, and (2) the tumor content of insulin-like growth factor-1 (IGF-1) and the rate of IGF-1-positive cells were significantly lower in the E2 group, but significantly higher in the TAM group than in the control group. It was concluded that the tumor content of IGF-1 and the proportion of IGF-I-positive cells were inversely correlated to the tumor growth and the 3H-thymidine labeling index in vivo.
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PMID:Effects of hormones on tumor growth and immunoreactive insulin-like growth factor-1 of estrogen receptor-positive human breast cancer (MCF-7) transplanted in nude mice. 175 78

Cathepsin D, an acidic protease normally acting in lysosomes, is overproduced both in vitro and in vivo in most breast cancer cells. The mechanism of gene regulation by estrogens and the biological and clinical significance of this overexpression in metastasis are reviewed. In MCF7 cells, cathepsin D is specifically and directly induced by estrogens and also induced by growth factors (EGF, IGF-I and bFGF), but this induction is dependent upon de novo protein synthesis. The mechanism of estrogen induction involves EREs located upstream from the gene. Our laboratory cloned the promoter region (-4kb) of cathepsin D of MCF7 cells and found EREs located in the proximal 5' region of the gene. In MDA-MB231 and BT20 cells, cathepsin D is overexpressed but not regulated by estrogens. Total cathepsin D concentration were assayed by IRMA in breast cancer cytosol routinely prepared for receptor assays. Several retrospective clinical studies indicate a significant correlation between high cathepsin D concentrations in the cytosol of primary breast cancer and further development of clinical metastasis. High cathepsin D concentration in the primary tumor may be either a consequence, or more likely a cause, of metastasis. Transfection experiments using cDNA-cathepsin D in rat tumoral cells facilitates their metastatic potential in nude mice (Garcia et al., Oncogene, 1990, 5, 1809-1814). The mechanism of cathepsin D action in facilitating metastasis is unknown and may involve proteolytic activity in an acidic compartment, and/or interaction with the Man 6P/IGFII receptor.
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PMID:[Mechanism of the overexpression of the cathepsin D gene in breast cancer and consequences in the metastatic process]. 182 91

We developed two different models based on in vitro co-culture of hormone-dependent and hormone-independent cell lines to simulate the cell population heterogeneity of human breast cancer tumours. Oestrogen-dependent (MCF-7, ZR 75.1) and oestrogen-independent cell lines (MDAMB-231 BT-20) were grown under serum-free conditions. Co-culture of hormone-dependent and hormone-independent cell lines resulted in an increased cell yield compared to single cell cultures carried out at the same seeding ratios. Such an increase was not affected by addition of oestradiol and single growth factors (EGF, bFGF and IGF-I). These results allow us to conclude that in a heterogeneous cell population like human breast tumours, interaction between hormone-dependent and hormone-independent cell lines may result in a complex regulation of cell growth.
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PMID:Interaction between hormone-dependent and hormone-independent human breast cancer cells. 183 28

The insulin-like growth factors IGF-I and IGF-II are potent mitogens for several breast tumor cell lines in culture. Additionally, both IGF-I and IGF-II mRNAs are easily detected in the majority of breast tumor specimens examined, while no breast cancer epithelial cell lines we have studied express authentic IGF-I mRNA, and few lines express IGF-II mRNA. Although receptors for insulin, IGF-I, and IGF-II have been described, there is significant cross-reactivity between the various receptors and ligands in the insulin/insulin-like growth factor family, and it is not clear which receptor or receptors are responsible for the biological effects of these growth factors in this system. Using an RNase protection assay, we examined breast tumor specimens and breast cancer epithelial cell lines for expression of mRNA encoding the type I and type II IGF receptors as well as the insulin receptor. Virtually all of the specimens examined expressed mRNA for all three receptors. We then examined estrogen-dependent MCF-7 cells for the mitogenic effects of IGF-I and II in the presence of antibodies to both the type I and type II receptors. alpha IR-3, a monoclonal antibody which blocks the type I receptor, abolished the mitogenic effects of both IGF-I and IGF-II. It did not, however, block the mitogenic effects of insulin. We conclude that type I and type II IGF receptors are ubiquitously expressed in breast cancer, and our experiments with MCF-7 cells suggest the mitogenic effects of both IGF-I and IGF-II are mediated via the type I IGF receptor.
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PMID:Insulin-like growth factor receptor expression and function in human breast cancer. 215 73

Estrogen sensitizes the MCF-7 estrogen-responsive breast cancer cell line to the mitogenic effect of insulin and the insulin-like growth factors (IGFs). This sensitization is specific for estrogen and occurs at physiological concentrations of estradiol. Dose-response experiments with insulin, IGF-I, and IGF-II suggested that the sensitization is mediated through the type I IGF receptor. Binding experiments with 125I-IGF-I and hybridization of a type I IGF receptor probe to RNA showed that the levels of the type I IGF receptor and its mRNA are increased 7- and 6.5-fold, respectively, by estradiol. IGF-I and estradiol had similar synergistic effects on other estrogen-responsive breast cancer cell lines, but IGF-I alone increased the proliferation of the MDA MB-231 cell line which is not responsive to estrogens. These experiments suggest that an important mechanism by which estrogens stimulate the proliferation of hormone-dependent breast cancer cells involves sensitization to the proliferative effects of IGFs and that this may involve regulation of the type I IGF receptor.
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PMID:Role of insulin-like growth factors and the type I insulin-like growth factor receptor in the estrogen-stimulated proliferation of human breast cancer cells. 217 37

The IGFs may be important autocrine, paracrine or endocrine growth factors for human breast cancer. IGF-I and II stimulate growth of cultured human breast cancer cells. IGF-I is slightly more potent, paralleling its higher affinity for the IGF-I receptor. Antibody blockade of the IGF-I receptor inhibits growth stimulation induced by both IGFs, suggesting that this receptor mediates the growth effects of both peptides. However, IGF-I receptor blockade does not inhibit estrogen (E2)-induced growth suggesting that secreted IGFs are not the major mediators of E2 action. Several breast cancer cell lines express IGF-II mRNA by both Northern analysis and RNase protection assay. IGF-II activity is found in conditioned medium by radioimmuno and radioreceptor assay, after removal of somatomedin binding proteins (BP) which are secreted in abundance. IGF-I is undetectable. BPs of congruent to 25 and 40 K predominate in ER-negative cell lines while BPs of 36 K predominate in ER-positive cells. Blockade of the IGF-I receptor inhibits anchorage-independent and monolayer growth in serum of a panel of breast cancer cell lines. Growth of one line (MDA-231) was also inhibited in vivo by receptor antibody treatment of nude mice. The antibody had no effect on growth of MCF-7 tumors. These data suggest that IGFs are important regulators of breast cancer cell proliferation and that antagonism of this pathway may offer a new treatment strategy.
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PMID:Regulation of breast cancer growth by insulin-like growth factors. 217 63

We previously demonstrated that antiestrogen 4-hydroxytamoxifen (OH-Tam) blocks the mitogenic activity of growth factors in breast cancer. We now investigate this mechanism by evaluating how OH-Tam affects growth factor binding and receptor tyrosine kinase activity. We show here that OH-Tam has an opposite effect on epidermal growth factor (EGF) and insulin-like growth factor-1 (IGF-1) binding in estrogen receptor (ER) positive cells. A decrease in IGF-1 binding sites may explain the reduced IGF-I mitogenic effect, whereas an increase in high affinity EGF binding associated with a decrease in in vitro receptor autophosphorylation rather favors the possibility of an alteration in EGF receptor tyrosine kinase activity. We conclude that OH-Tam may prevent growth factor action in ER+ cells both by modulating the concentration of growth factor binding sites and by altering growth factor receptor functionality.
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PMID:Mechanisms of 4-hydroxytamoxifen anti-growth factor activity in breast cancer cells: alterations of growth factor receptor binding sites and tyrosine kinase activity. 226 52


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