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

We studied the nature of insulin receptor binding in MCF-7 breast cancer cells. In both intact cells and solubilized receptor preparations, high-affinity insulin binding was seen. However, unlabeled insulin-like growth factor-I (IGF-I) was five-fold more potent in inhibiting 125I-insulin binding than insulin itself. With monoclonal antibodies to the insulin receptor, 30% of 125I-insulin binding was inhibited. In contrast when alpha-IR3, a monoclonal antibody that recognizes typical IGF-I receptor, was employed over 60% of 125I-insulin binding was inhibited. The B29-MAB-125I-insulin photoprobe was then cross-linked to MCF-7 membranes. Cross-linking was inhibited by both unlabeled insulin and IGF-I. Further, the B29-MAB-125I-insulin photoprobe cross-linked to MCF-7 membranes was strongly immunoprecipitated by alpha-IR3. Employing sequential affinity chromatography with insulin-Affi-gel followed by insulin receptor monoclonal antibody agarose, atypical insulin binding activity was separated from insulin receptor binding activity. This atypical receptor had intrinsic tyrosine kinase activity. Both insulin and IGF-I stimulated the phosphorylation of the receptor's beta subunit. In MCF-7 cells both IGF-I and insulin stimulated [3H]thymidine incorporation; alpha-IR3 blocked all of the IGF-I effect but only 50-60% of the insulin effect. This study demonstrates in MCF-7 cells that, in addition to typical insulin and IGF-I receptors, there is another receptor that binds both insulin and IGF-I with high affinity.
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PMID:High-affinity insulin binding to an atypical insulin-like growth factor-I receptor in human breast cancer cells. 131 20

Insulin-like growth factor-I (IGF-I) stimulated the growth and [3H]thymidine uptake in MCF-7 human breast cancer cells grown in serum- and growth factor-inactivated serum-containing media. Cotreatment of the cells with IGF-I plus 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) resulted in a significant decrease in mitogen-induced cell proliferation and [3H]thymidine uptake. Similar effects were observed for cells treated with 2,3,7,8-TCDD and IGF-I plus 17 beta-estradiol. The relative antimitogenic activities of 2,3,7,8-TCDD and related compounds followed the order 2,3,7,8-TCDD greater than 2,3,7,8-tetrachlorodibenzofuran (TCDF) greater than 1,2,7,8-TCDF greater than 1,3,7,8-TCDD which was similar to their aryl hydrocarbon (Ah) receptor binding affinities. The results showed that 2,3,7,8-TCDD did not alter the IGF-I receptor mRNA levels or the KD values for binding of [125I]IGF-I to the IGF-I receptor in MCF-7 cells. However, 2,3,7,8-TCDD significantly decreased the number of IGF-I-induced IGF-I receptor binding sites and this may play a role in the growth-inhibitory properties of 2,3,7,8-TCDD and related compounds and in the 'cross-talk' between the two endocrine-response pathways.
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PMID:Inhibition of insulin-like growth factor-I responses in MCF-7 cells by 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds. 133 6

Recent studies indicate that the insulin receptor (IR) content is higher in breast cancer cells than in normal mammary epithelial cells. This observation has been made both in tissue specimens from patients with breast cancer, and in various human cultured breast cancer cell lines. Investigations have now been undertaken to understand the role of progestins in the regulation of the IR and the closely related insulin like growth factors-I receptor (IGF-I-R). Pretreatment of T-47D cultured human breast cancer cell lines with progestins induced a time and dose dependent increase in IR content. This increase was due primarily to an effect of progestins to increase IR mRNA levels. Other steroid hormones including glucocortocoids, estrogen, and testosterone were without effect. In contrast to their up-regulation of the IR, progestins down-regulated the IGF-I-R at the level of mRNA. An analysis of the processes involved revealed that progestins increased the biosynthesis of a ligand for IGF-I receptor, IGF-II. IGF-II in turn down-regulated the IGF-I-R. Thus these studies indicate that progestins have important effects on both the IR and the IGF-I-R. The effects of progestins on these and other growth factor receptors, therefore, may have an important role in the biology of breast cancers.
Breast Cancer Res Treat 1992
PMID:Progestin regulation of insulin and insulin-like growth factor I receptors in cultured human breast cancer cells. 142 26

Antiestrogens are widely used in the management of hormonally responsive breast cancer in both adjuvant and palliative settings, and are currently being evaluated as chemopreventive agents. The classical mechanism of action of these drugs involves inhibition of estrogen-stimulated neoplastic cell proliferation by blockade of estrogen receptors present on breast cancer cells. This paper reviews recent clinical and laboratory data that suggest that the commonly used antiestrogen tamoxifen also acts to reduce serum IGF-I levels. Estrogens appear to play a permissive role in growth hormone (GH) release by the pituitary gland and GH is known to stimulate IGF-I expression by hepatocytes. It is therefore possible that blockade of estrogen receptors in the hypothalamic-pituitary axis by tamoxifen interferes with GH release, leading to reduced hepatic IGF-I expression. In view of results suggesting that IGF-I is a more potent mitogen than estradiol for breast cancer cells and data demonstrating a positive correlation between estrogen receptor level and IGF-I receptor level of breast cancer cells, the IGF-I lowering effect of tamoxifen may contribute to the cytostatic activity of the drug. The interrelationships between steroid hormone physiology and IGF-I physiology may have relevance to a variety of commonly used treatments for hormonally responsive cancers.
Breast Cancer Res Treat 1992
PMID:Tamoxifen reduces serum insulin-like growth factor I (IGF-I). 142 27

We have previously reported that insulin receptor expression is increased in human breast cancer specimens (V. Papa et al., J. Clin. Invest., 85:1503-1510, 1990). In the present study, in order to further understand the role of the insulin receptor in breast cancer, insulin receptor expression and function were characterized in three human breast cancer cell lines, MCF-7, ZR-75-1, and T-47D, and compared to a nonmalignant human breast epithelial cell line, 184B5. Insulin receptor content, measured by radioimmunoassay, was elevated 5- and 3-fold in MCF-7 and ZR-75-1 breast cancer cell lines, respectively, when compared to the nonmalignant cell line 184B5. In contrast, the insulin receptor content of T-47D cells was not increased. The increase in insulin receptor content in MCF-7 and ZR-75-1 cells was not due to amplification of the insulin receptor gene. Also, total insulin receptor mRNA content was not increased in breast cancer cells in respect to nonmalignantly transformed 184B5 breast epithelial cells. However, significant differences in the content of receptor mRNA species were observed. The insulin receptors in the breast cancer cell lines were functional: (a) In all 4 cell lines, high-affinity insulin-binding sites were detected, and, in concert with the insulin receptor radioimmunoassay data, binding capacity was highest in MCF-7 and then in ZR-75-1 cells. (b) In all cell lines, insulin stimulated insulin receptor tyrosine kinase activity. However, the effect of insulin was greater in breast cancer cell lines than in nonmalignant breast cells. (c) In all cell lines, insulin at concentrations of 1 nM or less stimulated [3H]thymidine incorporation. This effect of insulin was inhibited by 50% in MCF-7 cells and by 60% in 184B5 cells when alpha-IR3, a monoclonal antibody to the insulin-like growth factor I receptor, was present. In these cells, therefore, insulin was active via both its own receptor and the IGF-I receptor. In contrast, alpha-IR3 antibody was without effect in T-47D and ZR-75-1 cells, suggesting that in these cell lines insulin acted only via its receptor. In the breast cancer cells, MA-5, an agonist monoclonal antibody to the insulin receptor, stimulated [3H]thymidine incorporation. This present study indicates therefore that in breast cancer cell lines there are functional insulin receptors that regulate breast cancer cell growth.
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PMID:Insulin receptor expression and function in human breast cancer cell lines. 161 68

Insulin-like growth factor-I (IGF-I) receptors are present in breast cancer cells and may play a role in breast cancer cell growth. We have studied the effect of progestins on IGF-I receptors in T47D human breast cancer cells. T47D cells constitutively express high levels of progesterone receptors and are a model for studying the regulation of cellular functions by progestins. Treatment of T47D cells with either progesterone or the synthetic progestin promegestone (R5020) decreased IGF-I receptor content by approximately 50%, as measured by Scatchard analysis and receptor biosynthesis studies. In contrast to progestins, estradiol, dexamethasone, and dihydrotestosterone did not influence IGF-I receptor content. No effect of R5020 was seen after 12 h of incubation, a near-maximal effect was seen after 24 h, and greatest effects were seen after 72 h. R5020 decreased IGF-I receptor mRNA abundance, indicating that progestins acted at the level of gene expression. However, progestins also increased the secretion of IGF-II, a ligand for the IGF-I receptor. In contrast to IGF-II, T47D cells did not express IGF-I. The addition of exogenous IGF-II to T47D cells down-regulated both IGF-I receptor binding and IGF-I receptor mRNA abundance. This study indicates, therefore, that progestins regulate IGF-I receptors in breast cancer cells and suggests that this regulation occurs via an autocrine pathway involving enhanced IGF-II secretion.
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PMID:Progestins induce down-regulation of insulin-like growth factor-I (IGF-I) receptors in human breast cancer cells: potential autocrine role of IGF-II. 164 93

A radioimmunoassay for the human insulin-like growth factor-I (IGF-I) receptor was developed using a rabbit polyclonal antibody to the human IGF-I receptor and a highly purified IGF-I receptor. The purified receptor was radiolabeled with 125I-Bolton-Hunter reagent. Over 18% of the radiolabeled receptor was immunoprecipitated with the polyclonal antireceptor antibody. Purified IGF-I receptor concentrations as low as 5 ng/0.5 mL inhibited the radiolabeled IGF-I receptor binding. Purified insulin receptor weakly inhibited this binding, while the ligand IGF-I did not show inhibition. The radioimmunoassay was applicable to the measurements of IGF-I receptors in the Triton X-100 extracts of various tissues and cells. Breast cancer tissues and cells showed detectable IGF-I receptors, which correlated with IGF-I ligand binding. Receptor content was measurable in placenta and IM-9 cells, but receptor content was not measurable in liver and muscle extracts.
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PMID:Radioimmunoassay for human insulin-like growth factor-I receptor: applicability to breast carcinoma specimens and cell lines. 165 Apr 22

Several protooncogenes and suppressor genes and a variety of growth factors and their receptors have been shown to be mutated, deleted, or activated in human breast cancer. These changes may account for the unregulated growth of breast carcinoma cells. Insulin-like growth factors I and II (IGF-I, IGF-II) belong to a family of polypeptides with growth promoting properties and structural homology to insulin. They exert their mitogenic effects by binding to the IGF-I receptor and activating its tyrosine protein kinase. Other proteins that specifically bind the IGFs include the plasma membrane IGF-II receptor, which also binds lysosomal hydrolases, and several IGF-binding proteins which may serve to modulate IGF interactions with receptors. Breast cancer cell lines express IGF-I and IGF-II receptors and different patterns of binding proteins. IGF-I and IGF-II are each mitogenic for subsets of breast cancer cell lines. This effect is inhibited by antibodies directed against the IGF-I receptor. In breast tumors, IGF-I is expressed by stromal cells, but not carcinoma cells; it is not expressed by breast cancer cell lines. IGF-I is therefore a potential paracrine regulator of breast cancer cell growth. Similarly, IGF-II is expressed in breast tumors, predominantly in stromal cells, but sometimes also in carcinoma cells and in a subset of cell lines. Thus, IGF-II is also a potential paracrine regulator of breast cancer cell growth; in addition, it can be an autocrine regulator in some breast cancer cells.
Breast Cancer Res Treat 1991 May
PMID:Insulin-like growth factors in human breast cancer. 165 93

The hormone dependency of the MCF-7 breast cancer cell line, while extensively tested in liquid culture, has not been previously evaluated under conditions of anchorage-independent growth in serum-free media. Using the soft agar clonogenic assay, we demonstrate that physiologically relevant concentrations of estradiol (E2), progesterone (Pg), and prolactin (PRL) similarly stimulated MCF-7 cell colony formation in the absence of serum. Addition of an anti-insulin-like growth factor-I (IGF-I) antibody inhibited E2- and Pg-stimulated growth, while PRL action was not affected. Similar results were obtained with an anti-IGF-I receptor antibody, except that its inhibitory effect on Pg-induced colony formation was modest and not statistically significant. Administration of either an anti-transforming growth factor-alpha (TGF-alpha) antibody or an anti-epidermal growth factor (EGF) receptor antibody similarly inhibited E2-stimulated MCF-7 cell growth in soft agar, while neither antibody influenced Pg or PRL effects. Addition of TGF-beta 1, -beta 2, -beta 3 similarly suppressed MCF-7 cell colony formation in a dose dependent manner to a degree comparable to that observed with 4-OH-tamoxifen (4-OH-T). Furthermore, the growth inhibitory effect of 4-OH-T was completely reversed by an anti-TGF-beta antibody. We conclude that IGFs and TGF-alpha are important mediators of E2-stimulated MCF-7 cell growth in soft agar. IGFs may also be playing a role in Pg action, while neither growth factor is involved in PRL-stimulated colony formation. Finally, TGF-beta appears to be an important mediator of antiestrogen-induced inhibition of tumor growth.
Breast Cancer Res Treat 1991 Dec
PMID:Growth factor involvement in the multihormonal regulation of MCF-7 breast cancer cell growth in soft agar. 181 68

The lysosomal enzyme cathepsin-D (cath-D) and insulin-like growth factor-II (IGF-II), which share a common IGF-II/mannose-6-phosphate (M6P) transmembrane receptor, are both synthesized and secreted by breast cancer cells, upon which they might exert an intracrine/autocrine control on proliferation. We have evaluated the binding of 125I-immunopurified human cath-D in different breast cell membrane preparations. The concentration of high affinity M6P reversible binding sites (mean Kd, 0.85 nM) varied among the different breast cancer cells (0-0.82 pmol/mg membrane protein), but there was no correlation between the presence of steroid receptor and M6P-dependent binding. Cross-linking experiments with [125I]cath-D and [125I]IGF-II showed the formation of complexes with the 270,000 mol wt IGF-II/M6P receptor molecule which migrated, respectively, at 330,000 and 270,000 mol wt in 3-10% gradient sodium dodecyl sulfate-polyacrylamide gels. [125I]IGF-II cross-linking was increased by M6P (20% above control), whereas cath-D strongly inhibited IGF-II interaction by 80%. Conversely, IGF-II reduced [125I]cath-D cross-linking by 55%. Direct ligand binding on receptors transferred onto nitrocellulose sheets by Western blotting confirmed the interaction of both ligands on the same receptor molecule. By studying IGF-II's growth-promoting activity in these cells in a wide range of concentrations, we show that IGF-II triggers its mitogenic response via IGF-II/M6P receptor at low concentrations, whereas it is mainly acting via IGF-I receptor at high concentrations. Three lines of evidences lead us to that conclusion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interactions of cathepsin-D and insulin-like growth factor-II (IGF-II) on the IGF-II/mannose-6-phosphate receptor in human breast cancer cells and possible consequences on mitogenic activity of IGF-II. 217 99


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