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D Yee

Publications and source records attributed to D Yee.

At least 91 records · Page 5Linked to original sources
PubMed1992

Regulation of insulin-like growth factor-binding protein (IGFBP) expression by breast cancer cells: use of IGFBP-1 as an inhibitor of insulin-like growth factor action.

BACKGROUND: The insulin-like growth factors (IGFs) play an important role in normal growth and development. Evidence suggests they may also regulate the growth of several cancer cell types. This regulation is mediated by interactions between the receptors and ligands. There is now ample evidence to suggest that these interactions are also influenced by extracellular IGF-binding proteins (IGFBPs). Six different IGFBPs have been cloned. Some species may act to inhibit the mitogenic effects of the IGFs. Since breast cancer cells are responsive to the IGFs, it is possible that regulated expression of the IGFBPs affects tumor growth. Furthermore, inhibitory binding proteins could be used as neutralizers of IGF action. PURPOSE: We conducted this study to fully characterize the expression and hormonal regulation of IGF-binding protein expression in human MCF-7 breast cancer cells and to test the ability of purified IGFBP-1 to inhibit IGF-I action. METHODS: We used ribonuclease protection assays and Western ligand blotting to examine IGFBP expression in MCF-7 cells. The effect of IGF-I, IGFBP-1, and 17 beta-estradiol on serum-free cell growth was also studied. RESULTS: MCF-7 cells expressed IGFBP-2, IGFBP-4, and IGFBP-5 RNA and protein. These cells are dependent on estrogen for growth. In short-term culture, IGF-I can substitute for estrogen. Concomitant addition of IGF-I and estrogen enhanced stimulation above the level achieved by either factor alone. Estrogen also increased IGFBP production, making it unlikely that the IGFBPs induced by estrogen in MCF-7 cells could function as major inhibitors of IGF action. In contrast, exogenous addition of IGFBP-1 could block IGF-I-induced mitogenesis; this effect was reversible by excess IGF-I. CONCLUSIONS: The studies suggest that cancer cell growth may be regulated by endogenous IGFBP expression. Furthermore, the exogenous addition of the IGFBP-1 blocked IGF-I action and potentially could be used as a pharmacologic inhibitor of IGF action.

Blotting, Western↗
PubMed1992

Can the insulin-like growth factors regulate breast cancer growth?

Many laboratories have demonstrated that polypeptide growth factors stimulate human cancer cell growth in experimental systems. Despite this observation, a central question remains: can inhibition of peptide growth factor action inhibit tumor growth in humans? To answer this question, several other concerns must first be addressed. Which growth factors are critical for tumor growth? What are the specific cellular effectors for each growth factor? Can feasible therapies be designed to interrupt growth factor pathways? This issue of Breast Cancer Research and Treatment explores the relevance of the insulin-like growth factors to breast cancer cell growth.

Animals↗
PubMed1992

The insulin-like growth factor family of ligands, receptors, and binding proteins.

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.

Carrier Proteins↗
PubMed1992

The insulin-like growth factor binding proteins (IGFBPs) in human breast cancer.

Several lines of evidence suggest that IGFs are important regulators of breast cancer cell growth. Unlike other growth factors, the IGFs interact with specific binding proteins in all extracellular fluids. To date, six different IGFBPs have been cloned, although their exact physiological function is not understood. Experimental evidence accumulated over the past few years suggests that IGFBPs could function as modulators of IGF actions in a variety of systems. This includes breast cancer, since several groups have demonstrated the production of IGFBPs by human breast cancer cells. We have found that the pattern of expression of these binding proteins is heterogeneous and varies depending on the breast cancer cell ER status. We have also shown that estrogen is capable of regulating the expression of certain IGFBPs in MCF-7 cells. Specifically, estradiol enhanced the expression of IGFBP 2, 4, and 5, and decreased that of IGFBP-3 in this cell line. Since the IGFBPs can modulate IGF actions in different experimental systems, we and others have studied their potential role as inhibitors of IGF-induced mitogenesis in breast cancer cells. We have demonstrated that purified IGFBP-1 neutralized IGF-dependent growth of MCF-7 cells in a reversible manner. These results suggest that the IGFBPs might be used to inhibit IGF-mediated breast cancer proliferation.

Breast Neoplasms↗
PubMed1992

Gene expression of the insulin-like growth factors and their receptors in cultured human retinal pigment epithelial cells.

Insulin-like growth factors I and II (IGF I and II) are polypeptides with both growth-promoting and insulin-like metabolic effects. Immunoreactive IGF I is present in the retina and both IGF I and II are present in vitreal fluid. The type I and type II IGF receptors are also localized within the neural retina. The presence of IGFs and IGF receptors within the eye suggests a possible growth-promoting effect of IGFs on ocular tissues. IGF may enter the eye from the blood or, alternatively, arise from an ocular cell type which synthesizes and secretes IGF. IGF I and II mRNA synthesis in scleral cells and IGF I synthesis in rat retina suggests endogenous IGF production in the eye. We hypothesized that IGFs and IGF receptors are synthesized by one ocular cell type, the retinal pigment-epithelium (RPE). As a first step in studying IGF production by the RPE, we analyzed expression of the IGF and IGF receptor genes by cultured human RPE cells. Using Northern analysis, RNase protection and reverse-transcriptase polymerase chain reaction (RT-PCR), we found that cultured RPE cells synthesize mRNA for IGF I and the type I and type II IGF receptors.

Base Sequence↗
PubMed1992

Gene expression of the insulin-like growth factors and their receptors in human neuroblastoma cell lines.

Insulin-like growth factors (IGF) I and II are polypeptides with both growth-promoting and insulin-like metabolic effects. The developmentally specific expression of IGF I and II in the nervous system implies a role for these growth factors in neuronal growth and differentiation. In the present study, we analyzed IGF and IGF receptor mRNA transcripts from two related human neuroblastoma cell lines, SH-SY5Y and SK-N-SH. These cell lines provide a good in vitro model of neuronal development. Northern analysis of total RNA from each cell line revealed three IGF II mRNA transcripts (6.0, 4.8, and 1.8 kb), and one mRNA transcript each for the type I (11.0 kb) and type II (9.4 kb) IGF receptors. The size distribution of these multiple transcripts is similar to that found during normal human fetal development. These results establish both cell lines as good in vitro models for investigating the mechanisms which underly IGF gene expression during nervous system development.

Cell Differentiation↗
PubMed1991

Expression of insulin-like growth factor I, its binding proteins, and its receptor in ovarian cancer.

Insulin-like growth factor (IGF) I is a polypeptide hormone important in normal growth and development. Although IGF-I is a mitogen for many cancer cell lines, previous work has suggested that autocrine production of IGF-I is uncommon in cancers of epithelial origin. In this study, expression of IGF-I, its binding proteins, and its receptor were examined in ovarian cancer cell lines and tissues. Of 10 ovarian cancer cell lines, 3 (OVCAR-3, OVCAR-7, and PEO4) expressed IGF-I mRNA. RNase protection assays using probes derived from IGF-IA, IGF-IB, and alternate exon 1 IGF-I complementary DNAs demonstrated that these cells contained a predominant IGF-I transcript with an alternate first exon. RNA extracted from primary and metastatic ovarian cancer tissues also expressed IGF-I mRNAs (7 of 7) with the alternate first exon. IGF-I protein was detected in OVCAR-3-conditioned media; this activity was secreted in conjunction with several IGF-binding proteins (IGFBPs). IGFBP-2, IGFBP-3, an Mr 24,000 species, and an Mr 30,000 species could also be demonstrated in OVCAR-3. Type I IGF receptor mRNA was found in all 10 of the ovarian cancer cell lines and all 7 of the primary or metastatic ovarian cancer tissues. IGF-I was a mitogen for OVCAR-3, demonstrating the presence of a functional type I IGF receptor. These data show that all the necessary components for an IGF-I-mediated autocrine loop are expressed by ovarian cancer cells.

Blotting, Northern↗
PubMed1991

The insulin-like growth factors, their receptors, and their binding proteins in human breast cancer.

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.

Breast Neoplasms↗
PubMed1991

Identification of insulin-like growth factor binding proteins in breast cancer cells.

The insulin-like growth factors (IGFs) are potent mitogens for some breast cancer cell lines. Recent evidence suggests that IGF-induced mitogenesis may be influenced by specific IGF binding proteins (IGFBPs). In this study, breast cancer cell lines were examined for IGFBP protein and mRNA expression. Western ligand blot examination of conditioned media from breast cancer cell lines suggested that the IGFBP protein expression was heterogeneous. Although all breast cancer cell lines expressed a 24 kDa binding protein, MCF-7, an estrogen receptor positive (ER+) cell line, expressed a IGFBP compatible with reported sizes for IGFBP-2. Estrogen receptor negative (ER-) cells (MDA-MD-231, Hs578T) secreted IGFBPs consistent with sizes reported for IGFBP-1 and -3. Examination of mRNA expression supported these findings; IGFBP-2 was seen in all (4/4) ER+ cell lines while high levels of IGFBP-3 were found in ER- cell lines (3/5), although lower levels of IGFBP-3 mRNA could be found in some ER+ cell lines. In MCF-7 cells, steady state levels of IGFBP-3 mRNA were decreased by estradiol, while IGFBP-2 mRNA levels were slightly increased. These data suggest that IGFBP expression by breast cancer cells is heterogeneous, that the pattern of IGFBP expression is different between ER+ and ER- cell lines, and that in ER+ cells IGFBP mRNA may be regulated by estrogens. Thus, the IGFBPs may play an important role in mediating the mitogenic response of breast cancer cells to the IGFs.

Blotting, Northern↗
PubMed1991

Insulin-like growth factors in human breast cancer.

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 Neoplasms↗
PubMed1991

The prevalence and nature of podiatric problems in elderly diabetic patients.

To determine if diabetes in the elderly is associated with increased prevalence of podiatric problems, a random sample of diabetic patients (n = 74) was compared to a group of elderly non-diabetic patients (n = 79). The two groups were comparable in age (range 70-90 years), smoking habits, and consumption of alcohol. The mean duration of diabetes was 14.5 +/- 11.7 years (+/- SD), and mean serum fructosamine level was 3.3 +/- 0.66 mmol/L. The number of medical diagnoses and medications used was significantly higher in the diabetic group. Diabetic patients had modestly higher prevalence of neuropathy, vascular disease, kidney disease, and eye complications. The most common podiatric problem in both groups was elongated toenails. The prevalence of podiatric problems such as cellulitis, amputation, tinea pedia, onychomycosis, calluses, bunions, and hammer toe deformity were not increased in diabetic patients. Active foot ulcers were more common in diabetic patients (13/74 vs 5/79, P less than 0.05). It is concluded that diabetes in the elderly, unlike in young patients, increases the risk of foot problems only marginally.

Aged↗
PubMed1991

Objective measures of ocular irritation as a consequence of hydrogen sulphide exposure.

Hydrogen sulphide (H2S) exposure has been reported to adversely affect the eyes. Objective information regarding the extent of injury relative to varied exposure concentrations of H2S has not been published. The exfoliative eye cytology procedure has been demonstrated to provide quantitative information regarding the degree of ocular irritation and to allow for comparisons to be made between the irritants. This paper evaluates this procedure's efficiency in determining the degree of ocular irritation resulting from hydrogen sulphide exposure in rats.

Animals↗
PubMed1990

Insulin-like growth factor receptor expression and function in human breast cancer.

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.

Blotting, Northern↗
PubMed1990

Insulin-like growth factor I expression by tumors of neuroectodermal origin with the t(11;22) chromosomal translocation. A potential autocrine growth factor.

Expression of insulin-like growth factor I (IGF-I) mRNA by some tumor cell lines of neuroectodermal origin has been described. To further explore the significance of IGF-I mRNA expression in these tumors, a more extensive analysis was performed. Most (9 of 10) neuroectodermal tumor cell lines with a t(11;22) translocation (primitive neuroectodermal tumor [PNET], Ewing's sarcoma, esthesioneuroblastoma) expressed IGF-I mRNA, whereas 0 of 15 cell lines without the translocation (PNET, neuroblastoma) expressed IGF-I. Furthermore, inasmuch as all neuroblastoma (12 of 12) cell lines examined expressed IGF-II RNA, the pattern of IGF expression could distinguish between these closely related tumors. CHP-100, a PNET cell line with the t(11;22) translocation, was shown to secrete both IGF-I protein and an IGF binding protein, IGFBP-2. This cell line also expressed the type I IGF receptor mRNA, and blockade of this receptor by a monoclonal antibody (alpha IR3) inhibited serum-free growth. These data demonstrate that IGF-I expression is a property of neuroectodermal tumors with a t(11;22) translocation and that interruption of an IGF-I autocrine loop inhibits the growth of these tumor cells.

Cell Division↗