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M Pollak

Publications and source records attributed to M Pollak.

At least 55 records · Page 3Linked to original sources
PubMed1995

Regulation of IGFBP-3 expression in breast cancer cells and uterus by estradiol and antiestrogens: correlations with effects on proliferation: a review.

This paper reviews actions of antiestrogens on IGF physiology, and discusses the potential significance of the recent observations that (i) effects of antiestrogens on the uterus are correlated with their effects on uterine IGF-I and IGFBP-3 gene expression, and that (ii) the potent antiestrogen and growth inhibitor ICI 182,780 induces autocrine production of IGFBP-3 by estrogen receptor-positive breast cancer cells, while the growth stimulatory action of estradiol is associated with suppression of IGFBP-3 expression.

Breast Neoplasms↗
PubMed1995

Cloning and functional characterization of extracellular Ca(2+)-sensing receptors from parathyroid and kidney.

Parathyroid cells recognize and respond to (i.e., "sense") minute perturbations in the extracellular ionized calcium concentration (Ca2+o), but the mechanisms underlying this process have remained obscure. Recently, we employed expression cloning in Xenopus laevis oocytes to isolate a cDNA coding for a Ca2+o-sensing receptor from bovine parathyroid. Like the native receptor, the cloned Ca2+o-sensing receptor stimulates phospholipase C (PLC) in a G-protein-dependent manner with a nearly identical pharmacological profile. Its deduced amino acid sequence confirms that it is a member of the superfamily of G-protein-coupled receptors (GPR). Transcripts for the receptor are expressed in parathyroid and other tissues that sense Ca2+o (viz., kidney and thyroidal C-cells) as well as those that have no known role in extracellular Ca2+ homeostasis, such as the brain. The availability of the cDNA clone for the Ca2+o-sensing receptor made it possible to test the hypothesis that mutations in the gene encoding the human homolog of the receptor cause inherited disorders of mineral ion metabolism. Familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT) are, in fact, caused by mutations that reduce the activity of the receptor when they are present in the heterozygous and homozygous states, respectively. In contrast, we have subsequently discovered a family in which a form of autosomal dominant hypocalcemia results from an activating mutation in the receptor gene. The Ca2+-sensing receptor, therefore, permits Ca2+o to play a "hormonelike" role as an extracellular first messenger in addition to its well described role as an important intracellular second messenger.

Amino Acid Sequence↗
PubMed1995

The cloning of extracellular Ca(2+)-sensing receptors from parathyroid and kidney: molecular mechanisms of extracellular Ca(2+)-sensing.

The parathyroid cell detects changes in the extracellular ionized calcium concentration (Ca2 + o) with exquisite sensitivity, but the mechanisms through which it senses Ca2 + o have remained obscure. Recently, we isolated a cDNA encoding a Ca2 + o-sensing receptor from bovine parathyroid using expression cloning in Xenopus laevis oocytes. The expressed receptor stimulates phospholipase C and has a pharmacological profile almost identical to that of the native receptor. Furthermore, its deduced amino acid sequence confirms that it belongs to the superfamily of G-protein-coupled receptors. Receptor transcripts are present in parathyroid and other tissues sensing Ca2 + o (e.g., kidney and thyroidal C-cells) as well as those not known to be involved in Ca2+ homeostasis (viz., in the brain). We have also shown that mutations in the receptor cause three inherited disorders of calcium metabolism: Familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT) result from inactivating mutations, when present in the heterozygous and homozygous states, respectively, whereas an autosomal dominant form of hypocalcemia is due to an activating mutation. Thus this Ca2 + o-sensing receptor permits Ca2+o to act as an extracellular, first messenger in addition to its better known role as an intracellular second messenger.

Animals↗
PubMed1995

Molecular mechanisms underlying the sensing of extracellular Ca2+ by parathyroid and kidney cells.

Mineral ion homeostasis in mammalian species is maintained by a complex mechanism comprising sensors of the extracellular calcium concentration (Ca2+0) (i.e. parathyroid cells) as well as effectors that modify their translocation of mineral ions into and out of the extracellular fluid (e.g. kidney) in response to calciotropic hormones. Indirect evidence accumulated over the past decade suggested that parathyroid cells sense Ca2+0 through a cell surface receptor coupled to intracellular second messenger systems via one or more guanine nucleotide regulatory (G) proteins. More recently, Brown et al. employed expression cloning in Xenopus laevis oocytes to isolate a cDNA encoding a Ca2+0-sensing receptor from bovine parathyroid. The expressed receptor activates phospholipase C in a G-protein dependent manner and shows pharmacological properties almost identical to those of the native parathyroid receptor. Agonists for the receptor include not only divalent cations (e.g. Ca2+ and Mg2+) but also trivalent cations and even organic polycations such as neomycin. The deduced amino acid sequence of the cloned receptor confirms that it is a member of the superfamily of G-protein-coupled receptors. Receptor transcripts are present in parathyroid as well as in kidney, thyroid and brain. Therefore, this receptor may mediate the sensing of Ca2+0 not only by parathyroid cells but also by other tissues directly regulated by Ca2+0 (e.g. the thyroidal C cells and certain kidney cells) as well as those not currently known to be involved in calcium homeostasis (viz. in the brain).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Extraosseous Ewing's sarcoma.

Extraosseous Ewing's sarcoma is an undifferentiated round-cell sarcoma that is indistinguishable histologically from Ewing's sarcoma of bone. Despite this similarity, it has been accepted as a distinct clinicopathologic entity. The authors describe a 53-year-old man who presented with extraosseous Ewing's sarcoma of the left subcostal chest wall. The lesion was demonstrated by radiography and computed tomography and confirmed by pathological examination.

Humans↗
PubMed1994

Somatostatin analogue octreotide enhances the antineoplastic effects of tamoxifen and ovariectomy on 7,12-dimethylbenz(alpha)anthracene-induced rat mammary carcinomas.

The efficacy of tamoxifen and ovariectomy in the management of breast cancer is limited by the resistance of many neoplasms to these endocrine therapies and by the fact that initially responding tumors often escape from control during long-term treatment. We evaluated the effect of coadministration of the somatostatin analogue octreotide, which has single agent activity in several in vivo and in vitro breast cancer models, on the antineoplastic actions of tamoxifen and ovariectomy on 7,12-dimethylbenz(alpha)anthracene-induced mammary tumors. Rats received tamoxifen (0.5 mg/kg twice weekly s.c.), octreotide (10 micrograms/kg/h for 6 weeks by osmotic minipump), or the combination 7 weeks following 7,12-dimethylbenz(alpha)anthracene administration. The number of tumors per animal and the sum of the volumes of palpable tumors per animal were significantly less in the combination treatment than in the others. In ovariectomized rats the marked regression of established tumors in the initial 4 weeks after ovariectomy was frequently followed by tumor regrowth. However, continuous infusion of octreotide (50 micrograms/kg/h for 6 weeks postovariectomy) significantly (P < 0.01) suppressed this regrowth. Our data suggest that octreotide enhances the antitumor effects of tamoxifen or ovariectomy in the 7,12-dimethylbenz(alpha)anthracene mammary cancer model.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1994

Enhancement of tamoxifen-induced suppression of insulin-like growth factor I gene expression and serum level by a somatostatin analogue.

Mitogenic responsivity of many neoplasms to IGF-I has been detected in a variety of in vivo and in vitro experimental systems. This has led to the proposal that pharmacological reduction of IGF-I bioactivity might represent a novel non-cytotoxic palliative therapy. We recently reported that tamoxifen, a commonly used antiestrogen antineoplastic agent, significantly suppresses IGF-I gene expression and serum IGF-I levels. We report here that the somatostatin analogue octreotide, previously demonstrated to reduce acromegalic levels of IGF-I towards normal, decreased serum IGF-I to 70 +/- 4% (mean +/- SD) of control values and hepatic IGF-I expression to 65 +/- 10% of control values in a short-term non-acromegalic rat model. Tamoxifen reduced serum IGF-I to 74 +/- 12% of control values and hepatic IGF-I expression to 46 +/- 9% of control values in this model, but the combination of octreotide and tamoxifen reduced serum IGF-I concentration to 49 +/- 10% of control values and hepatic IGF-I gene expression to 12 +/- 9% of control values. The levels of serum IGF-I and hepatic IGF-I gene expression were significantly less in animals treated with the combination of octreotide and tamoxifen than in animals treated with either agent alone (p < .01). This combination represents a novel pharmacological strategy for suppressing IGF-I gene expression that may be relevant to the design of clinical trials.

Animals↗
PubMed1994

Uterotrophic actions of estradiol and tamoxifen are associated with inhibition of uterine insulin-like growth factor binding protein 3 gene expression.

We have recently shown that uterine insulin-like growth factor I (IGF-I) gene expression is up-regulated by tamoxifen, a uterotrophic partial antagonist to the estrogen receptor, but down-regulated by the complete estrogen receptor antagonist ICI 182780, which causes uterine involution. This result is consistent with prior reports indicating that the uterotrophic effects of estradiol are mediated at least in part by estradiol-stimulated uterine IGF-I gene expression. We demonstrate here that the uterotrophic agents estradiol and tamoxifen each suppress expression of the IGF binding protein 3 (IGFBP-3) gene in uterus to less than one-third of control values, while oophorectomy or administration of the complete estrogen receptor antagonist ICI 182780, both of which result in uterine involution, are associated with a greater than 3-fold stimulation of uterine IGFBP-3 gene expression. The data reveal a negative correlation between uterine weight and uterine IGFBP-3 gene expression as well as reciprocal regulation by estradiol of expression in uterus of the genes encoding IGF-I and IGFBP-3. In vitro, IGFBP-3 protein accumulation in media conditioned by primary uterine cultures was decreased by estradiol treatment and increased by ICI 182780 treatment. Together, these observations provide a novel mechanism by which estradiol and antiestrogens modulate uterine IGF-I physiology that is consistent with the view that the mitogenic activity of IGF-I is reduced in the presence of IGFBP-3. The uterotrophic toxicity of chronic estradiol or tamoxifen treatment may be causally related to both the inhibition of uterine IGFBP-3 expression and the stimulation of uterine IGF-I expression by these compounds.

Animals↗
PubMed1994

Metastatic behavior of the RIF-1 murine fibrosarcoma: inhibited by hypophysectomy and partially restored by growth hormone replacement.

BACKGROUND: We recently demonstrated that hypophysectomy profoundly inhibits metastatic behavior in the MGH-OGS murine osteosarcoma model and speculated that this effect is related at least in part to ablation of the growth hormone (GH)-insulin-like growth factor I (IGF-I) axis. PURPOSE: In this study, we determined whether the administration of GH to animals rendered GH and IGF-I deficient by hypophysectomy attenuates the inhibitory effects of hypophysectomy on metastatic behavior. METHODS: Metastatic behavior was assayed by counting visible metastases in lungs 3 weeks after tail vein injection of RIF-I fibrosarcoma cells to control mice (n = 29), hypophysectomized mice (n = 19), and hypophysectomized mice administered 0.05 microgram/g body weight recombinant human GH twice daily (n = 21). RESULTS: Twenty of 21 hypophysectomized mice receiving GH, eight of 19 hypophysectomized mice not receiving GH, and 26 of 29 controls had grossly visible pulmonary metastases 3 weeks after intravenous injection of 5 x 10(5) cells; mean numbers +/- SD of gross metastases were 38.4 +/- 11.3, 6.4 +/- 2.2, and 13.1 +/- 2.8 in the three groups, respectively. The presence (P < .005, chi-square test) and number (P = .0003, Mann-Whitney U test) of metastases were significantly reduced in hypophysectomized hosts compared with control hosts and were significantly higher in hypophysectomized, GH-replaced hosts compared with hypophysectomized hosts (P < .001, chi-square test; P = .011, Mann-Whitney U test), while the difference in presence and extent of metastases between control and hypophysectomized, GH-replaced hosts was not statistically significant. CONCLUSIONS: These data support the hypothesis that the status of the host with respect to GH and/or GH-dependent factors such as IGF-I influences the metastatic behavior of certain neoplasms. IMPLICATIONS: Our results raise the possibility that compounds that reduce GH output or interfere with GH action, such as somatostatin analogues, GH antagonists, IGF antagonists, and GH-releasing hormone antagonists, may suppress metastatic behavior of certain neoplasms.

Animals↗
PubMed1993

Insulin-like growth factor I gene expression in the uterus is stimulated by tamoxifen and inhibited by the pure antiestrogen ICI 182780.

Estrogen-induced uterine insulin-like growth factor I (IGF-I) expression has been demonstrated to mediate at least in part the uterotrophic action of estradiol. We studied the effects of tamoxifen, a partial antagonist to the estrogen receptor widely used in the treatment of breast cancer, and ICI 182780, a pure antagonist to the estrogen receptor, on uterine weight and uterine IGF-I gene expression in the rat. Tamoxifen increased uterine weight to 125% of control values and doubled uterine IGF-I expression. In contrast, ICI 182780 reduced uterine weight to 60% of control and uterine IGF-I gene expression to 13% of control. These results demonstrate for the first time that uterine IGF-I expression is a molecular marker that correlates with the effects of partial agonists and antagonists to the estrogen receptor on the uterus. Furthermore, the induction of uterine IGF-I expression by tamoxifen provides a molecular mechanism to account for the uterotrophic effects which are commonly seen with tamoxifen therapy and which have been associated with endometrial neoplasia.

Animals↗
PubMed1993

In vivo inhibition of insulin-like growth factor I gene expression by tamoxifen.

Tamoxifen, a partial antagonist to the estrogen receptor, is widely used in the treatment of breast cancer and is currently being evaluated as a breast cancer preventative agent in large-scale clinical trials. Recent clinical research has demonstrated that tamoxifen administration is associated with a reduction of serum insulin-like growth factor I (IGF-I) concentration. We demonstrate here that tamoxifen, when administered in an in vivo experimental system previously used to demonstrate its cytostatic effect on breast cancer cell proliferation, inhibits the expression of the IGF-I gene in common target organs for breast cancer metastasis. Furthermore, while our prior experimental studies have demonstrated an inhibitory effect of tamoxifen on growth hormone output, we show here for the first time that the suppression of IGF-I gene expression associated with tamoxifen administration is in part a consequence of a pituitary-independent action of the drug. Because IGF-I is a potent mitogen for breast cancer cells, this newly described activity of tamoxifen may contribute to its antineoplastic properties, particularly with regard to inhibition of metastasis seen both in animal models and clinically.

Animals↗
PubMed1993

The human insulin-like growth factor-binding protein 4 gene maps to chromosome region 17q12-q21.1 and is close to the gene for hereditary breast-ovarian cancer.

The gene for insulin-like growth factor-binding protein 4 (IGFBP4) codes for a serum protein that binds to the family of insulin-like growth factors and modulates their activity. It has been mapped by in situ hybridization to chromosome region 17q12-q21.1. We have developed a CA-repeat polymorphism from a cosmid clone containing IGFBP4. By linkage analysis, IGFBP4 maps to the chromosome 17q interval THRA1-D17S579. This interval also contains the gene for hereditary breast-ovarian cancer, BRCA1. Genetic recombination between IGFBP4 and BRCA1 places IGFBP4 centromeric to the cancer susceptibility gene and effectively excludes it as a candidate gene for BRCA1. IGFBP4 is, however, one of the closest known centromeric markers for BRCA1; the estimated recombination fraction is 0.015. IGFBP4 and D17S579 together define a 2.8-cM interval that contains BRCA1.

Base Sequence↗
PubMed1993

Suppression of serum insulin-like growth factor-1 levels in breast cancer patients during adjuvant tamoxifen therapy.

Serial IGF-1 levels in patients prior to and during adjuvant tamoxifen (TAM) treatment were followed in a retrospective study. Serum IGF-1 levels were determined by radioimmunoassay in 19 patients taking TAM and 19 controls, matched for age, body weight and other treatments. IGF-1 levels at 2 years were significantly lower in TAM patients (P < or = 0.05) compared to control patients. We observed a significant mean drop from pretreatment to treatment IGF-1 levels by 19.9% in the TAM group (P < or = 0.005), but also noted a mean 11.4% decline in the control group (P < or = 0.025). A subgroup analysis suggested that premenopausal were relatively resistant to the IGF-1 lowering effects of TAM as compared to postmenopausal women.

Adult↗