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)

Hs578T human breast cancer cells secrete insulin-like growth factor binding protein 3 (IGFBP-3) as the major BP species. In addition, cell surface-associated IGFBP-3 is demonstrable by the use of cell monolayer affinity cross-linking or immunoperoxidase staining of the cell surface with a specific polyclonal anti-human IGFBP-3 antibody (alpha IGFBP-3 gamma 1). In this study, we have demonstrated that regulation of Hs578T IGFBP-3 by IGF peptides is specific, non-receptor mediated, and post-translational by showing: 1) dose-dependent increase of IGFBP-3 in conditioned media (CM) following addition of IGF-I and -II (maximum 13 fold increase at 100 ng/ml), but not by insulin up to 1 mg/ml; 2) no change in CM IGFBP-3 level by [Gln3,Ala4,Tyr15,Leu16] IGF-I, which has decreased affinity for IGFBPs; 3) no change in IGFBP-3 mRNA following addition of IGFs; 4) release of cell surface-associated IGFBP-3 into CM by the addition of IGFs, but not by [Gln3,Ala4,Tyr15,Leu16]IGF-I. These studies demonstrate that IGF peptides regulate CM concentrations of IGFBP-3 through non-receptor mediated dissociation of cell surface-associated IGFBP-3.
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PMID:Non-receptor mediated, post-transcriptional regulation of insulin-like growth factor binding protein (IGFBP)-3 in Hs578T human breast cancer cells. 128 Feb 12

It has been proposed that the insulin-like growth factors (IGFs) can act as autocrine and/or paracrine growth promoters in breast cancer. To investigate this hypothesis, we infected early passage MCF-7 cells with a retroviral vector containing the coding sequence for the IGF-II preprohormone along with a constitutive cytomegalovirus promoter sequence. These cells do not normally express IGF-I or IGF-II. After infection with the retroviral vector, several single cell clones were analyzed. Seven of nine isolated clones expressed very high levels of IGF-II mRNA. Biologically active IGF-II protein was easily detectable in the medium conditioned by the IGF-II-expressing clones, and IGF receptors were down-regulated in these. All IGF-II-expressing clones showed marked morphological changes in anchorage-dependent culture, growing in large clumps and as free-floating colonies. The cells also cloned in soft agar in the absence of estrogen, while the wild-type MCF-7 cells and control cells infected with an irrelevant DNA sequence showed none of these properties. alpha IR-3, an antibody that blocks the type I IGF receptor, inhibited the growth of IGF-II-expressing clones in serum-free medium. This model demonstrates that IGF-II can serve as an autocrine growth stimulant in breast cancer epithelial cells and that IGF-II overexpression may be capable of mediating malignant progression in human breast cancer.
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PMID:Insulin-like growth factor-II overexpression in MCF-7 cells induces phenotypic changes associated with malignant progression. 131 Jul 98

Female BDF1 mice inoculated with MXT (3.2) estrogen independent mouse mammary carcinoma were treated for three weeks with microcapsules of the luteinizing hormone-releasing hormone (LH-RH) agonist [D-Trp6]LH-RH, the antagonist SB-75, the somatostatin analog RC-160, or combinations. The lack of estrogen dependence of the tumor was proved by bilateral surgical ovariectomy, which had no effect. In two experiments, treatment with 25 micrograms/day doses of each analog alone resulted in a significant inhibition of tumor growth as shown by a 40-53% inhibition of tumor volumes, 38-43% decrease in tumor weights, and histological signs of tumor regression. However, the combination of SB-75 or [D-Trp6]LH-RH with somatostatin analog RC-160 caused greater reduction of tumor volume (68 and 61%) or tumor weights (59 and 56%), than single analogs, and histologically the occurrence of apoptosis and decrease in AgNOR numbers was more pronounced in the groups receiving combination therapy. Specific binding sites for [D-Trp6]LH-RH, EGF, and IGF-I were demonstrated in the tumor membranes. The binding capacity of LH-RH receptors was decreased by treatment with the analogs, the greatest down-regulation being caused by combination therapy. A significant decrease in EGF binding capacity was observed after treatment with the LH-RH analogs, alone or especially in combination with somatostatin analog RC-160. The combination of these analogs also caused a reduction in IGF-I receptors. The finding that LH-RH agonists and antagonists and somatostatin analogs inhibit the growth of estrogen independent mammary tumors, and that combinations are more effective than single analogs, might be of practical importance in human breast cancer therapy.
Breast Cancer Res Treat 1992
PMID:Growth inhibition of estrogen independent MXT mouse mammary carcinomas in mice treated with an agonist or antagonist of LH-RH, an analog of somatostatin, or a combination. 135 75

Cytogeneticists first proposed that the karyotypic abnormalities identified on chromosomes 1, 3, 6, 11, 13, 16, 17, and 18 supported a genetic basis for breast cancer. Such abnormal banding patterns, however, may represent either loss-of-function or gain-of-function molecular events. RFLP analyses have since confirmed that 20-60% of primary and spontaneous human breast tumors exhibit allelic losses on these same chromosomes, although the exact genes involved at these chromosomal sites remain largely unknown. Knowledge gained about the Rb-1 and p53 tumor suppressor genes at 13q14 and 17p13 in breast and other human tumors supports the paradigm that for any chromosomal locus, allelic loss associated with a mutation in the remaining tumor allele signifies an involved tumor suppressor gene. Given this paradigm, there are nearly a dozen putative breast tumor suppressor genes under active investigation, with most investigators now focusing on various chromosome 17 loci. Among the known proto-oncogenes found activated in breast cancer, amplification of c-erbB-2 at 17q21 is the most widely studied and clinically significant gain-of-function event uncovered to date, occurring in about 20% of all primary breast tumors. The involvement of this overexpressed membrane receptor has engendered interest in related tyrosine kinase receptors, such as EGFR, IR, and IGF-I-R, as well as their respective ligands, which may be overexpressed in a greater fraction of tumors, contributing to the autocrine and paracrine regulation of breast cancer growth and metastasis. New attention is being given to the potentially oncogenic function of structurally altered nuclear transactivating steroid hormone receptors, such as ER, whose overexpression has long been used to determine endocrine therapy and prognosis for individual breast cancer patients. While c-myc was one of the first known proto-oncogenes to be found amplified and overexpressed in human breast cancers, the actual incidence and clinical significance of its activation remain disputed and in need of further study. Lastly, we can expect greater clarification about the importance of various 11q13 genes found coamplified in nearly 20% of primary breast cancers, and pursuit into the intriguing possibility that a cyclin-encoding gene represents the overexpressed locus of real interest in this amplicon. Virtually all of these important genetic abnormalities identified thus far are associated with but not restricted to human breast cancers. The absence of identifiable molecular defects relating to the tissue specificity of this malignancy must be considered a substantial gap in our basic understanding of breast carcinogenesis.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Activated oncogenes and putative tumor suppressor genes involved in human breast cancers. 136 56

We report the expression of insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) by breast cancer cells and normal breast tissue in vivo. N-nitrosomethyl-urea (NMU)-induced rat mammary tumors synthesize mRNAs for IGF-II and IGFBP-2, -3, and -4. In contrast, normal lactating breast contains only IGFBP-2 and IGF-II messages; IGFBP-3 and -4 mRNAs are absent in this tissue. IGF-I and IGFBP-1 mRNAs are not expressed in either NMU tumors or in normal breast. This is the first report of in vivo expression of IGFBPs and IGF-II messages in breast tumors.
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PMID:Expression of messenger RNA for insulin-like growth factors and insulin-like growth factor binding proteins by experimental breast cancer and normal breast tissue in vivo. 137 57

Four estrogen receptor-positive (ER+) [MCF-7, T47D, ZR75 and BT474] and 3 ER- [Hs578T, MDA-MB-468 and MDA-MB-231] human breast cancer cell lines were examined for expression of the IGFBP-5 and IGFBP-6 genes. Northern blot analysis revealed that all cell lines, except MDA-MB-231, expressed IGFBP-5 mRNA. IGFBP-6 mRNA, however, was expressed only by the ER- cell lines. Western immunoblotting indicated that the previously unidentified 31-kDa and 32-kDa IGF binding species secreted by these cell lines are IGFBP-5. The levels of IGFBP-4 and IGFBP-5 were increased in MCF-7 cells by estradiol and IGF-I, respectively, indicating that these BPs may contribute to the growth stimulatory response to these mitogens.
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PMID:Identification of the insulin-like growth factor binding proteins 5 and 6 (IGFBP-5 and 6) in human breast cancer cells. 137 5

The insulin-like growth factors (IGFs) have important roles in normal cellular growth and development. The IGFs have also been implicated in regulation of tumor cell growth. Two ligands, IGF-I and IGF-II, have been identified that are expressed in both fetal and adult tissues. They interact with at least two specific cell surface receptors. The type I IGF receptor is homologous to the insulin receptor in structure and has tyrosine kinase activity. The type II receptor is identical to the mannose-6-phosphate receptor known to be important in the trafficking of lysosomal enzymes; its role in IGF signal transduction is not clear. Furthermore, a hybrid receptor composed of subunits from the insulin receptor and the type I IGF receptor have been identified. In addition to these receptors, six different IGF binding proteins have been identified, which modulate the activity of the IGFs in various ways. Thus, there is great potential for complex interactions between the family members that could ultimately regulate normal and neoplastic cell growth.
Breast Cancer Res Treat 1992
PMID:The insulin-like growth factor family of ligands, receptors, and binding proteins. 138 4

In order to evaluate the potential role of calcium as an intracellular messenger for IGF-I and TGF-alpha action on breast cancer cell proliferation, we determined whether these growth factors induce any change in [Ca2+]i using fura-2 loaded cells. The hormone independent BT-20 and MDA-MB-231 cells were refractory to the mitogenic actions of exogenously added IGF-I and TGF-alpha. TGF-alpha administration, however, stimulated [Ca2+]i transients in the BT-20 cells. IGF-I and TGF-alpha stimulated DNA synthesis in the MCF-7 and T47D cells. These growth factors did not, however, stimulate any changes in [Ca2+]i in these cells. These data support the idea that receptor-mediated phospholipid hydrolysis does not serve a major signalling function for driving human breast cancer cells into DNA synthesis.
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PMID:TGF-alpha and IGF-I effects on calcium ion transients in human breast cancer cells. 139 17

A number of growth factors have been implicated in the control of the proliferation of breast cancer cells and some have been reported to mediate the proliferative effects of oestradiol. MCF-7 cells were treated with growth factors in the presence and absence of oestradiol. Oestradiol increased the response of cells to the proliferative effects of epidermal growth factor (EGF), transforming growth factor alpha (TGF-alpha) and basic fibroblast growth factor (bFGF). Platelet derived growth factor (PDGF) and cathepsin D had no effect in the presence or absence of oestradiol while TGF-beta slightly reduced the stimulation by oestradiol. In the absence of oestradiol, there was little effect of combinations of growth factors although the effects of bFGF and IGF-I were additive. In the presence of oestradiol, the effects of bFGF and TGF-alpha were additive whereas bFGF acted as an IGF-I antagonist. Overall, bFGF had the greatest effect on cell proliferation although this was less marked than the previously described effect of the IGFs and insulin. The effects of oestradiol on the sensitivity of cells to the proliferative effects of bFGF did not appear to result from regulation of bFGF receptor expression.
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PMID:Modulation of the proliferative response of breast cancer cells to growth factors by oestrogen. 141

Experimental evidence suggests that human breast cancer cells can be regulated by the IGF-I and IGF-II present in the tumor stromal elements and/or by the endogenous tumor cell IGF-II in a paracrine or autocrine fashion. Thus, blockade of the receptor signalling pathway could lead to diminished tumor growth. Blockade of the type I IGF receptor by a monoclonal antibody (alpha IR3) has been used as a strategy to demonstrate the importance of the IGF pathway. Although alpha IR3 could not block serum-free growth of breast cancer cell lines, it could inhibit anchorage independent growth in most cell lines in the presence of serum. In vivo, alpha IR3 administered at the time of tumor cell inoculation could inhibit MDA-MB-231 tumor formation in athymic mice; however, inhibition of established tumors was not seen. Moreover, alpha IR3 could not inhibit tumor formation of the MCF-7 cell line in vivo. These results suggest that blockade of the type I IGF receptor can inhibit the growth of some breast cancer cells both in vitro and in vivo. Future anti-growth factor strategies include the combination of anti-IGF receptor antibodies with IGF neutralizing modalities, the dual blockade of growth factor receptors (epidermal growth factor receptor and type I IGF receptor), and combinations of steroid hormone antagonists and anti-growth factor treatments to maximize tumor inhibition.
Breast Cancer Res Treat 1992
PMID:Interference of the IGF system as a strategy to inhibit breast cancer growth. 142 19


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