Search PubMed⌕ Search

Biomedical subjects

M E Lippman

Publications and source records attributed to M E Lippman.

At least 109 records · Page 6Linked to original sources
PubMed1992

Mastectomy versus breast-conserving therapy in the treatment of stage I and II carcinoma of the breast: a randomized trial at the National Cancer Institute.

PURPOSE: Mastectomy versus excisional biopsy (lumpectomy) plus radiation for the treatment of stage I and II breast cancer was compared in a prospective randomized study. PATIENTS AND METHODS: From 1979 to 1987, 247 women were randomized and 237 were treated on this study. All patients received a full axillary dissection and all node-positive patients received adjuvant chemotherapy with cyclophosphamide and doxorubicin. Radiation consisted of external-beam therapy to the whole breast with or without supraclavicular nodal irradiation followed by a boost to the tumor bed. RESULTS: The minimum time on the study was 18 months and the median time on the study was 68 months. No differences in overall survival or disease-free survival were observed. Actuarial estimates at 5 years showed that 85% of mastectomy-treated patients were alive compared with 89% of the lumpectomy/radiation patients (P2 = .49; 95% two-sided confidence interval [CI] about this difference, 0% to 9% favoring lumpectomy plus radiation). The probability of failure in the irradiated breast was 12% by 5 years and 20% by 8 years according to actuarial estimates. Of 15 local breast failures, 14 were treated with and 12 were controlled by mastectomy; the ultimate local-regional control was similar in both arms of the trial. CONCLUSION: These data add further weight to the conclusion that breast conservation using lumpectomy and breast irradiation is equivalent to mastectomy in terms of survival and ultimate local control for stage I and II breast cancer patients.

Adult↗
PubMed1992

Insulin-like growth factor-II overexpression in MCF-7 cells induces phenotypic changes associated with malignant progression.

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.

Breast Neoplasms↗
PubMed1991

Post-transcriptional destabilization of estrogen receptor mRNA in MCF-7 cells by 12-O-tetradecanoylphorbol-13-acetate.

The effect of 12-O-tetradecanoylphorbol-13-acetate (TPA) on the regulation of the estrogen receptor (ER) was investigated in this study. After treatment with 100 nM TPA the concentration of receptor protein was measured using an enzyme immunoassay. By 24 h the receptor protein declined by about 80% from a level of approximately 236 fmol of ER/mg of protein in control cells to 50 fmol of ER/mg of protein in cells treated with TPA. Similar results were obtained with an estrogen receptor ligand binding assay. After removal of TPA, the level of ER returned to control values. 4-alpha-Phorbol, a compound related to TPA, had no effect on ER. The effects of TPA on ER expression appear to be mediated by activation of protein kinase C as H-7, an inhibitor of protein kinase C, blocks these effects. In addition to the effect on ER protein, TPA treatment also resulted in a decrease in the steady-state level of ER mRNA as determined by a RNase protection assay. The metabolic inhibitor cycloheximide was unable to prevent the TPA-induced decrease in ER mRNA. Transcription run-off experiments demonstrated that TPA had no effect on ER gene transcription. A half-life study demonstrated that TPA decreased ER mRNA half-life by a factor of 6 from approximately 4 h in control cells to 40 min in TPA-treated cells. These data suggest that the decline in ER expression is mediated by post-transcriptional destabilization of ER mRNA.

Cycloheximide↗
PubMed1991

Growth factor messenger RNA expression by human breast fibroblasts from benign and malignant lesions.

Breast tumors are a complex mix of epithelial, stromal, and vascular elements. We examined primary cultures of breast fibroblasts derived from benign and malignant lesions for expression of various growth factors. All fibroblast cultures, regardless of whether they were derived from benign or malignant lesions, expressed platelet-derived growth factor A chain, basic fibroblast growth factor, fibroblast growth factor 5, and transforming growth factor beta 1 mRNA. None expressed platelet-derived growth factor B chain or transforming growth factor alpha mRNA. However, examination of mRNA expression for the insulin-like growth factors revealed that 7 of 8 fibroblasts derived from benign lesions expressed insulin-like growth factor I (IGF-I) mRNA, while only 1 of 9 fibroblasts derived from malignancies expressed IGF-I mRNA. The opposite picture was seen for insulin-like growth factor II (IGF-II) mRNA expression, in which 1 of 9 benign-derived fibroblasts expressed IGF-II mRNA, while 5 of 9 malignant-derived fibroblasts expressed IGF-II. This correlated with previous in situ hybridization data, which showed IGF-I mRNA expression confined to the stroma of benign breast tissue. PDGF treatment of tumor fibroblasts resulted in a 3-fold increase in IGF-II mRNA. Thus there was an apparent dichotomy between IGF-I mRNA expression in the majority of fibroblasts derived from benign lesions and IGF-II mRNA expression in the majority of tumor-derived fibroblasts. Since the insulin-like growth factors are potent mitogens for breast tumor epithelial cells, this further supports the notion of a paracrine growth-promoting role for the insulin-like growth factors in breast lesions and suggests that IGF-II may be the more important growth promoter in malignant lesions.

Breast Diseases↗
PubMed1991

Tumor growth dependent on Kaposi's sarcoma-derived fibroblast growth factor inhibited by pentosan polysulfate.

A neoangiogenic response is critical for the unrestricted growth of solid tumors beyond a few millimeters in diameter. Release of adequate growth-stimulating activity from tumor cells is obviously required for the stimulation of blood vessel growth, and blockade of such stimulatory activity should repress tumor growth at the microscopic level. To test this hypothesis and to study appropriate inhibitors, we used a human adrenal cancer cell line (SW-13/K-fgf) engineered to secrete Kaposi's sarcoma-derived fibroblast growth factor (K-FGF), which we previously showed to induce growth of highly vascularized subcutaneous tumors in animals by autocrine and paracrine stimuli. In the present study, we tested different polysulfates for their selective inhibition of proliferation induced by K-FGF versus proliferation independent of K-FGF. Suramin and dextran sulfate showed slight selective inhibition of K-FGF-induced proliferation, ie, inhibition three- and five-fold greater, respectively, than the inhibition of proliferation independent of K-FGF. In contrast, heparin was inactive. The heparin analogue pentosan polysulfate (PPS), however, showed selective inhibition that was more than 2000-fold greater. The inhibitory effects of PPS on growth of SW-13/K-fgf cells, as well as endothelial cells, were fully reversible by an excess of added FGF. Daily intraperitoneal injections of PPS were tolerated well by athymic nude mice and prevented growth of subcutaneous SW-13/K-fgf tumor xenografts. PPS will be a useful tool to elucidate the effects of FGFs in vitro and in vivo and appears to be a prototype for the development of tumoricidal therapy based on targeting of growth factors.

Adrenal Gland 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

Induction of transforming growth factor beta by the antiestrogens droloxifene, tamoxifen, and toremifene in MCF-7 cells.

We have previously shown that transforming growth factor beta (TGF beta) is a hormonally regulated negative growth factor in estrogen responsive MCF-7 human breast cancer cells. We have now compared the antiestrogens tamoxifen, droloxifene (3-hydroxytamoxifen), and toremifene in their ability to induce the secretion of autoinhibitory TGF beta by MCF-7 cells. The main results are as follows: induction of TGF beta secretion by droloxifene is about two to three times higher than by identical concentrations of tamoxifen or toremifene. A 5-10 times higher concentration of tamoxifen or toremifene than droloxifene is necessary to reach a similar induction of TGF beta secretion. In contrast to tamoxifen, intermittent application of droloxifene is as effective as continuous treatment in inducing TGF beta secretion. We conclude from these data that TGF beta proteins represent markers of antiestrogen action and might also play a pivotal role in their mechanism of action. Droloxifene is a more effective inducer of TGF beta and a more potent growth inhibitor for estrogen responsive human breast cancer cells than tamoxifen and toremifene in vitro. Therefore, droloxifene might also possess a higher antiestrogenic potential in treatment of human breast cancer.

Antineoplastic Agents↗
PubMed1991

The EGF receptor system as a target for antitumor therapy.

Monoclonal anti-EGF receptor antibodies, EGF receptor antibodies coupled to toxins, TGF alpha-toxin conjugates and tyrosine kinase inhibitors show great potential as antitumor agents. These compounds are effective inhibitors of the EGF receptor system as it functions in the mitogenic stimulation of malignant cells. The effectiveness of cell growth inhibition mediated by anti-EGF receptor antibody and tyrosine kinase inhibitors may prove to be limited and selective. This is in view of the possibility that malignant cell proliferation may be controlled by various mechanisms instead of that which involves the EGF receptor system, despite the expression of both EGF receptor and TGF alpha in the same cell. Other growth control mechanisms could involve hormone receptor systems such as estradiol and the estrogen receptor, oncogene activation or other growth factor-receptor systems. In those malignancies in which growth control resides in the EGF-receptor system, antitumor therapy using monoclonal anti-EGF receptor antibodies and tyrosine kinase inhibitors is a possibility worth pursuing. The effectiveness of immunotoxins and TGF alpha-toxin conjugates may only require the presence of EGF receptor and not be limited to those cells whose growth is controlled exclusively by the EGF receptor system. Nonspecific toxicity may, however, limit the use of these compounds. Further studies assessing the extent of such a toxicity are in order. In the face of the preceding reservations, however, one must not overlook the potential for great achievement as this novel therapeutic avenue is traversed.

Animals↗
PubMed1991

The role of erbB-2 and its ligands in growth control of malignant breast epithelium.

A wealth of recently derived information has strongly implicated the protooncogene erbB-2 (also termed HER-2 or neu) and its protein product as critically involved in human breast cancer as well as other important epithelial malignancies. Because of its substantial homology with the EGF receptor, erbB-2 has long been assumed to encode a growth factor receptor, although until recently definitive identification of ligand(s) has remained elusive. Both in a mutated form and when overexpressed in a non-mutated form, erbB-2 is capable of inducing malignant transformation of many target cells including immortalized breast epithelium. We have recently identified and purified a 30 kDa size growth factor secreted by some human breast cancer cells. The factor is related to transforming growth factor-alpha (TGF-alpha) in its ability to bind to the epidermal growth factor (EGF) receptor (though with about 10 fold lower apparent affinity), its ability to phosphorylate EGF receptor and its ability to induce cloning of normal rat kidney (NRK) fibroblasts. However, it is distinct from TGF-alpha as determined by peptide mapping and its ability to induce activation of erbB-2. TGF-alpha and EGF are incapable of directly inducing phosphorylation of erbB-2. However, in a variety of spontaneously occurring tumor cells as well as cell lines transfected with erbB-2 prepared in our laboratory, 30 kDa glycoprotein (gp30) is capable of inducing direct phosphorylation of erbB-2. The ability to induce phosphorylation of erbB-2 is not inhibited by an anti-EGF receptor blocking antibody. In cells that overexpress erbB-2, the gp30 low concentrations is stimulatory of both standard mitogenesis assays and in clonogenic assays. At higher concentrations, the ligand is growth inhibitory in both of these assays. Because of the ability of gp30 to compete for binding with antibodies directed against erbB-2 which inhibit growth, the gp30 ligand is capable of reversing antibody-induced inhibition of growth. In addition, the gp30 ligand can overcome inhibitory effects seen in cells which overexpress erbB-2 which are induced by extracellular domain fragments of the erbB-2 receptor, once again suggesting a specific pathway of action for the gp30 ligand mediated for interaction with erbB-2.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Comparison of urinary transforming growth factor-alpha in women with disseminated breast cancer and healthy control women.

In an effort to explore the use of polypeptide growth factors as potential markers for cancer detection, we have identified the presence of transforming growth factor-alpha (TGF-alpha) in pooled urine of patients with metastatic breast cancer by a commercial radioimmunoassay (RIA) based on a rabbit antiserum raised to the C-terminal 17aa synthetic fragment of rat TGF-alpha. This TGF-alpha RIA detected both high molecular weight (HMW) and low molecular weight (LMW) forms of TGF-alpha in the conditioned media of a breast cancer cell line (MDA-MB-231) and in the urine of healthy women and those with breast cancer. The ratio of HMW to LMW species of TGF-alpha by RIA after Bio-Gel P-100 chromatography was approximately equal in pooled urine samples from both healthy women and those with breast cancer, and in the conditioned media from the cell line MDA-MB-231. Using established procedures for concentrating urinary proteins from 24-h urine samples by adsorption onto methyl-bonded microparticulate silica and selective elution by acetonitrile, TGF-alpha RIA results from women with disseminated breast carcinoma were compared with those of healthy pre- and post-menopausal control women. Analysis indicated a median TGF-alpha value of 981 ng/g urinary creatinine for urine samples from cancer patients (range 608 to 1737) and 642 ng/g creatinine (range 417 to 941) for control urine samples. Although the difference was statistically significant (p less than 0.05), urinary TGF-alpha detection with this assay method appears to have limited usefulness as a diagnostic marker for metastatic human adenocarcinoma of the breast.(ABSTRACT TRUNCATED AT 250 WORDS)

Biomarkers, Tumor↗
PubMed1990

Regulation of proliferation, invasion and growth factor synthesis in breast cancer by steroids.

Endogenous ovarian estrogens and progestins appear to play a critical role in the development and progression of breast cancer. Local productions of growth factors probably also contribute to malignant proliferation, while production and activation of collagenolytic enzymes may be equally critical for local invasive processes. The current review focuses on characterization of growth factor-receptor systems operant in normal and malignant breast epithelium. In addition, the determinants of local invasion are reviewed: attachment, modality, and proteose secretion. Finally, data are discussed concerning the regulation of both proliferation and invasion by hormones and antihormonal agents in hormone-dependent breast cancer. The results suggest new potential pharmacologic targets to explore to suppress onset and progression of breast cancer.

Animals↗
PubMed1990

Direct interaction of a ligand for the erbB2 oncogene product with the EGF receptor and p185erbB2.

The erbB2 oncogene encodes a 185-kilodalton transmembrane protein whose sequence is similar to the epidermal growth factor receptor (EGFR). A 30-kilodalton factor (gp30) secreted from MDA-MB-231 human breast cancer cells was shown to be a ligand for p185erbB2. An antibody to EGFR abolished the tyrosine phosphorylation induced by EGF and transforming growth factor-alpha (TGF-alpha) but only partially blocked that produced by gp30 in SK-BR-3 breast cancer cells. In two cell lines that overexpress erbB2 but do not expresss EGFR (MDA-MB-453 breast cancer cells and a Chinese hamster ovary cell line that had been transfected with erbB2), phosphorylation of p185erbB2 was induced only by gp30. The gp30 specifically inhibited the growth of cells that overexpressed p185erbB2. An antibody to EGFR had no effect on the inhibition of SK-BR-3 cell colony formation obtained with gp30. Thus, it appeared that gp30 interacted directly with the EGFR and erbB2. Direct binding of gp30 to p185erbB2 was confirmed by binding competition experiments, where gp30 was found to displace the p185erbB2 binding of a specific antibody to p185erbB2. The evidence described here suggests that gp30 is a ligand for p185erbB2.

Animals↗