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M Pollak

Publications and source records attributed to M Pollak.

At least 73 records · Page 4Linked to original sources
PubMed1996

Silencing of the mammary-derived growth inhibitor (MDGI) gene in breast neoplasms is associated with epigenetic changes.

Recently, we reported that breast cancer cell lines fail to express the gene encoding the fatty acid binding protein mammary derived growth inhibitor (MDGI) and that transfection with an MDGI expression vector results in suppression of the malignant phenotype, suggesting that MDGI is a tumor suppressor gene. We also demonstrated that homozygous deletion and point mutation are not common mechanisms for silencing of the MDGI gene in human breast neoplasms. We now report that hypermethylation of HpaII and HhaI sites upstream of the first exon of the MDGI gene, and a SacII site in the first intron, occurs frequently in human breast cancer cell lines. This distinct methylation pattern is associated with loss of transcription and is reversible by treatment with 5-aza-deoxycytidine. Primary breast tumors also exhibited methylation of the SacII site (19 of 35, 54.3%) and the HpaII and HhaI sites (21 of 35, 66%). Hypermethylation of these sites was correlated with the absence of MDGI mRNA in these tumors. Our results suggest that epimutation of the MDGI gene leads to silencing, which, in turn, may initiate or contribute to progression of breast cancer.

Azacitidine↗
PubMed1996

[Sweet's syndrome].

Explore the source record for details and available documents.

Arthritis, Infectious↗
PubMed1996

Pregnancy-dependent growth of mammary tumors is associated with overexpression of insulin-like growth factor II.

We demonstrate that although IGF-II gene expression is approximately 3-fold higher in 9,10-dimethyl-1,2-benzanthracine (DMBA)-induced rat mammary tumors (MTs) than in nonneoplastic breast tissue, IGF-II mRNA abundance in DMBA-induced MTs is approximately 130-fold higher in pregnant as compared to nonpregnant hosts. This correlated with accelerated tumor growth in pregnant hosts. Immunohistochemical studies of DMBA-induced MTs with an anti-IGF-II antibody showed an intense staining of tumor cells for IGF-II, whereas a very low staining signal was observed for normal epithelial cells in the lobules. A similar immunostaining pattern was observed in three of three human ductal cancers and adjacent normal breast tissue obtained during pregnancy. DMBA-induced MTs expressed high levels of type I receptor for IGFs as determined by Northern blots. In vitro studies confirmed that IGF-II is a mitogen for neoplastic epithelial cells derived from DMBA-induced MTs. These results demonstrate that hormonal changes associated with pregnancy accelerate breast cancer cell proliferation in the DMBA-induced MT model and suggest that this acceleration is mediated by up-regulation of IGF-II expression within neoplasms.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1996

Reduced growth of human breast cancer xenografts in hosts homozygous for the lit mutation.

Insulin-like growth factor I (IGF-I) is a potent breast cancer mitogen. Growth hormone (GH) up-regulates hepatic IGF-I gene expression and circulating IGF-I level. Tissue IGF bioactivity is influenced not only by circulating IGF-I and IGF-II levels but also by autocrine and paracrine production of these growth factors and by IGF binding proteins. There is considerable person-to-person variability in GH-IGF-I physiology. Both laboratory and epidemiological data are consistent with the hypothesis that the host GH-IGF-I axis influences breast cancer behavior, but such an effect has not been directly demonstrated. To determine whether breast cancer growth in an in vivo model is influenced by the host GH-IGF-I axis, we compared the growth of human MCF-7 breast cancer cells in control mice to that in mice homozygous for lit, a missense mutation resulting in loss of function of the pituitary GH-releasing hormone receptor and secondary suppression of GH and IGF-I. Breast cancer growth was significantly reduced in lit/lit animals compared to control hosts [tumor size (mean +/- SD) on day 39,444 +/- 82 versus 845 +/- 444 mm3, respectively; P < 0.001, Mann-Whitney U test]. These data demonstrate that in our model, host GH-IGF-I axis physiology plays a role in determining breast cancer behavior. The results a) suggest that patient-to-patient variability in GH-IGF-I physiology may contribute to the large variability between patients regarding breast cancer behavior, and b) motivate clinical trials of novel hormonal treatment strategies that target the GH-IGF-I axis.

Animals↗
PubMed1996

Estradiol and antiestrogens regulate a growth inhibitory insulin-like growth factor binding protein 3 autocrine loop in human breast cancer cells.

MCF-7 human breast cancer cells are commonly used to model tissues responsive to estrogens and antiestrogens. We examined the effects of estradiol and the antiestrogen ICI 182780 on MCF-7 cell proliferation and insulin-like growth factor binding protein 3 (IGFBP-3) gene expression. ICI 182780-induced growth inhibition was associated with increased transcription of the IG-FBP-3 gene, increased IGFBP-3 mRNA abundance, and increased IGFBP-3 protein accumulation in the conditioned medium. The growth stimulatory effect of estradiol was associated with opposite effects, and the correlation between cellular proliferation and IGFBP-3 mRNA abundance was strong (r = -0.91). Recombinant IGFBP-3 inhibited basal and estradiol-stimulated MCF-7 cell proliferation, and an IGFBP-3 antisense oligodeoxynucleotide abolished antiestrogen-induced growth inhibition. These results provide evidence for an estradiol and antiestrogen-regulated IGFBP-3 growth inhibitory autocrine pathway in MCF-7 cells.

Breast Neoplasms↗
PubMed1996

Gitelman's syndrome is genetically distinct from other forms of Bartter's syndrome.

In the past the term Bartter's syndrome has been used to describe a spectrum of inherited renal tubular disorders with hypokalemic metabolic alkalosis and overlapping and additional clinical and biochemical features. Pathogenesis remained uncertain until recently Gitelman's syndrome, the hypokalemic-hypomagnesemic variant with hypocalciuria, was linked to the gene encoding the thiazide-sensitive Na-Cl-cotransporter (TSC) located on chromosome 16q. Various mutations in the TSC gene were identified in patients with Gitelman's syndrome. To clarify whether different forms of hypokalemic tubular disorders (HTD) represent variable phenotypes of a common genetic defect, we performed linkage analyses in 17 families with different symptoms of HTD with four highly polymorphic chromosome 16 DNA markers closely linked to the TSC gene. Linkage of Gitelman's syndrome to the TSC locus was confirmed in our families with a maximum two-point Lod score Z = 4.70 (theta = 0.001) for marker locus D16S526. Highly negative LOD scores were obtained at this locus in our families with classic Bartter's syndrome (Z = 9.89, theta = 0.001) and hyperprostaglandin E syndrome (Z = -11.24, theta = 0.001). Our data prove that Gitelman's syndrome is genetically distinct from classic Bartter's syndrome and hyperprostaglandin E syndrome. It remains unknown if classic Bartter's syndrome and hyperprostaglandin E syndrome are caused by a common genetic defect.

Adolescent↗
PubMed1996

Enhancement of the anti-neoplastic effects of tamoxifen by somatostatin analogues.

Tamoxifen is useful in the treatment of breast cancer, but its effects in metastatic disease are rarely long term, and development of resistance to the drug is common. In vitro and in vivo data demonstrate anti-neoplastic (anti-proliferative) effects of somatostatin analogues, which may occur via binding to somatostatin receptors on the neoplastic cells, and/or via reductions in insulin-like growth factor-1 bioactivity. Moreover, several lines of evidence from in vitro and in vivo studies indicate that the long-acting somatostatin analogue octreotide enhances the anti-neoplastic effects of anti-oestrogenic agents such as tamoxifen. The anti-oestrogen-somatostatin approach appears to have a favourable long-term toxicity profile. Large-scale clinical trials are currently being planned to investigate the efficacy of combined tamoxifen plus octreotide therapy compared to tamoxifen alone in patients with breast cancer.

Animals↗
PubMed1996

A role for insulin-like growth factor binding protein 5 in the antiproliferative action of the antiestrogen ICI 182780.

Insulin-like growth factors (IGFs) are potent mitogens for breast cancer cells. Although IGF-binding proteins (IGFBPs) are known to regulate access of IGFs to IGF receptors, their precise biological actions are poorly defined. We observed that the potent antiestrogen ICI 182780 (ICI) increased IGFBP-5 mRNA by 2-3-fold in 9,10-dimethyl-1,2-benzanthracene-induced mammary tumors in vivo. In vitro studies showed that growth inhibition of MCF-7 human breast cancer cells induced by ICI was associated with increased transcription of the IGFBP-5 gene, increased IGFBP-5 mRNA abundance, and increased IGFBP-5 protein accumulation in the conditioned medium. Growth stimulation following estradiol exposure was associated with opposite effects. An IGFBP-5 antisense oligodeoxynucleotide significantly decreased IGFBP-5 accumulation in conditioned media and enhanced MCF-7 cell DNA synthesis. Furthermore, this antisense oligodeoxynucleotide attenuated both antiestrogen-induced IGFBP-5 accumulation and antiestrogen-induced growth inhibition. These data demonstrate that estradiol down-regulates and ICI up-regulates an autocrine IGFBP-5 growth inhibitory pathway in MCF-7 cells and suggest that IGFBP-5 plays a role in modulation of proliferation of breast cancers by estrogens and antiestrogens.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1996

Regulation of insulin-like growth factor I receptor expression by the pure antiestrogen ICI 182780.

Insulin-like growth factor I (IGF-I) is a mitogen for human breast cancer cells both in vivo and in vitro. We demonstrate here that the antiestrogen ICI 182780 (ICI) at 10(-8) m decreases IGF-I receptor (IGF-IR) mRNA levels by 70% after treatment for 48 h. Measurements of mRNA stability indicate that the half-life of IGF-IR mRNA is approximately 3 h. Estradiol treatment increases the half-life of the IGF-IR mRNA to approximately 6 h and the level of IGF-IR gene transcription by 1.8-fold, whereas ICI treatment not only decreases the IGF-IR transcription rate by 50% but also decreases the IGF-IR mRNA half-life to less than 3 h. Affinity labeling studies with [125I]-IGF-I show 35% increased labeled IGF-I to MCF-7 cell membrane following estradiol treatment and 40% decreased labeling following ICI treatment. We also demonstrate that ICI attenuates IGF-I-stimulated growth. Our data suggest that attenuation of IGF-I responsivity by ICI may be due in part to reducing the IGF-IR expression.

Breast Neoplasms↗
PubMed1995

Tumor suppressor activity of the gene encoding mammary-derived growth inhibitor.

The gene encoding mammary-derived growth inhibitor (MDGI), a protein previously purified from bovine mammary gland and shown to have modest antiproliferative activity for human breast cancer cells in vitro, is demonstrated to function as a potent tumor suppressor gene. Human breast cancer cells transfected with a MDGI expression construct exhibited differentiated morphology, reduced proliferation rate, reduced clonogenicity in soft agar, and reduced tumorgenicity in nude mice relative to mock-transfected or untransfected controls. We mapped the human homologue of this gene to chromosome 1p33-35, a locus previously shown to exhibit frequent loss of heterozygosity in human breast cancer. MDGI immunoreactivity was detected in epithelial cells of human breast tissue, but not on ductal carcinoma cells on the same sections. Our results suggest that MDGI is a strong candidate for the distal 1p breast tumor suppressor gene. Furthermore, as prior reports have demonstrated that MDGI is hormonally regulated in breast epithelial cells and maximally expressed at the time of maximal differentiated function (just prior to lactation), MDGI is a candidate mediator of the differentiating effect of pregnancy on breast epithelial cells, which may be involved in the protective effect of early parity on subsequent breast cancer incidence.

Animals↗