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V Fantl

Publications and source records attributed to V Fantl.

13 recordsLinked to original sources
PubMed1995

Mice lacking cyclin D1 are small and show defects in eye and mammary gland development.

Using homologous recombination, mice lacking cyclin D1 were generated by replacing most of the first exon of the Cyl-1 gene with sequences encoding neomycin resistance. Cyl-1(-1-) mice were viable and fertile but consistently smaller than their heterozygous or wild-type littermates. The nullizygous animals also showed two distinctive abnormalities: a severe retinopathy caused by impaired development of all layers of the retina and, in the mammary gland during pregnancy, a marked reduction in acinar development accompanied by a failure to lactate. Approximately 50% of animals also had a malformation of the jaw that manifested itself as a misalignment of the incisor teeth. Mouse embryo fibroblasts isolated from 14 day nullizygous, heterozygous, or wild-type embryos and grown under standard conditions showed similar cell-cycle and growth characteristics. Thus although cyclin D1 kinase activity may facilitate G1 progression, it is not essential for the development of most tissues and organs, and only a few specialized cell lineages are demonstrably sensitive to its absence.

Animals↗
PubMed1995

Amplification of chromosome band 11q13 and a role for cyclin D1 in human breast cancer.

In this paper we describe how research on the mouse mammary tumor virus model of breast cancer resulted in the identification of an amplified region of DNA on human chromosome 11 band q13. This amplification occurs in approximately 15% of primary breast cancers. Several candidate oncogenes map within the amplicon but by analysing expression of these genes a strong case can be made for a role for cyclin D1 in tumorigenesis. Immunohistochemical staining indicates that cyclin D1 is expressed at elevated levels in around 40% of breast cancers, including those with the 11q13 amplification. The potential function of cyclin D1 as a regulator of early cell division cycle events would be consistent with a role in neoplasia.

Blotting, Southern↗
PubMed1995

Chromosome 11q13 markers and D-type cyclins in breast cancer.

One in six primary human breast cancers has DNA amplification centered on the cyclin D1 gene (CCND1) on chromosome 11q13. This genetic abnormality is preferentially associated with estrogen-receptor positive tumors and may define a sub-class of patients with an adverse prognosis. Although CCND1 has the credentials of a cellular oncogene, being a target for chromosomal translocation and retroviral integration, the 11q13 amplicon encompasses several other markers and CCND1 is not the only candidate for the key gene on the amplified DNA. To assess their relative importance, we have constructed a physical map of the amplified DNA and compared the extent and frequency of amplification across the region. Since it is likely that the gene providing the selective force for amplification will be expressed at elevated levels, we have also examined expression of both RNA and protein. By these criteria, cyclin D1 remains the strongest candidate for the key oncogene on the amplicon and we are currently investigating the functional consequences of its over-expression.

Breast Neoplasms↗
PubMed1994

Amplification and overexpression of cyclin D1 in breast cancer detected by immunohistochemical staining.

Immunohistochemical staining with a monoclonal antibody against human cyclin D1 can be used to identify breast cancers that have an amplification of the q13 region of chromosome 11. In general, the intensity of staining is directly proportional to the degree of DNA amplification. In two unusual tumors, in which the CCND1 locus is highly amplified but staining is relatively weak, it appears that the DNA has undergone rearrangement and that the amplified/rearranged CCND1 allele may have reduced transcriptional activity. More significantly, the immunohistochemical technique identifies additional tumors in which the cyclin D1 gene is overexpressed with only marginal or undetectable increases in copy number, implying that other mechanisms can lead to deregulated expression. These results suggest that the frequency of overexpression is much higher than previously concluded from DNA-based analyses and that more than one-third of human breast cancers may contain excessive levels of cyclin D1. The technique we describe should facilitate the detection of this abnormality in a clinical setting and clarify its prognostic significance.

Alleles↗
PubMed1993

Chromosome 11q13 abnormalities in human breast cancer.

Amplification of markers centred on band q13 of human chromosome 11 is a consistent feature in a subset of oestrogen receptor positive breast cancers. Although the amplification was initially scored via FGF3/INT2, which has strong credentials as a mammary oncogene, current data suggest that some other gene on 11q13 provides the driving force for amplification. Here we have reviewed our understanding of the amplified DNA, the genes it encompasses and the evidence in favour of two candidate oncogenes, CCND1 and EMS1. As well as being among the most frequently amplified markers in the region, these genes are expressed at elevated levels as a consequence of amplification, and their predicted functions would be consistent with a role in tumorigenesis. Irrespective of the final conclusions regarding their biological relevance, the overexpression of CCND1 or EMS1 should provide a more amenable assay for the amplification and help to clarify its clinical significance.

Animals↗
PubMed1992

Nonuniform expression of a mouse mammary tumor virus-driven int-2/Fgf-3 transgene in pregnancy-responsive breast tumors.

We have developed transgenic mice in which expression of the mouse int-2/Fgf-3 gene is regulated by a single long terminal repeat from mouse mammary tumor virus. Such mice contain and transmit a replica of the activated int-2/Fgf-3 allele present in a spontaneous mammary tumor from a BR6 mouse. Although free of infectious mouse mammary tumor virus and with a different genetic background, the transgenic mice develop pregnancy-responsive mammary epithelial proliferations that are similar to the early stages of tumorigenesis in the BR6 strain. Histological examination revealed that most of these tumors showed pronounced tubular and acinar structures, features usually associated with morphological differentiation. In some cases, the tumors were locally invasive, causing disruption of the dermis which manifested itself as local hair loss. In situ hybridization showed that patterns of transgene expression in the abnormal glands were markedly nonuniform. In contrast, mouse mammary tumor virus-induced neoplasms showed more uniform expression of int-2/Fgf-3, as did the urogenital epithelial proliferations that occur among males of this transgenic line. These data suggest that mammary tumors in virally infected animals may depend primarily on autocrine stimulation by the int-2/Fgf-3 gene product, whereas both autocrine and paracrine mechanisms may contribute to tumors and hyperplasias found in transgenic animals.

Animals↗
PubMed1991

D11S287, a putative oncogene on chromosome 11q13, is amplified and expressed in squamous cell and mammary carcinomas and linked to BCL-1.

Approximately 15 to 20% of primary breast cancers and an even higher proportion of squamous cell carcinomas of the head and neck show amplification of DNA markers on band q13 of human chromosome 11. However, known genes within the amplified region, such as the FGF-related oncogenes INT-2 and HST-1, are very rarely expressed in these tumors. Here we show that another candidate oncogene, designated D11S287, implicated in the pathogenesis of parathyroid adenomas, is also amplified in breast cancers. Significantly, it is consistently coamplified with INT-2 and HST-1 in 36 out of 202 primary tumors, including one case in which the amplified unit did not encompass the translocation breakpoint marker BCL-1. This implies that D11S287 is on the same side of the breakpoint as INT-2, and pulsed-field gel electrophoresis indicates that D11S287 is less than 250 kb from the BCL-1 marker. Since D11S287 RNA was present at elevated levels in a group of tumors and cell lines in which the 11q13 region is amplified, it may be the key oncogene on this amplified unit, and could also be activated by BCL-1 translocations.

Blotting, Southern↗
PubMed1990

Gene amplification on chromosome band 11q13 and oestrogen receptor status in breast cancer.

We have analysed DNA from 183 primary breast cancers for amplification or rearrangement of a number of cellular proto-oncogenes, focusing primarily on a cluster of markers on the long arm of chromosome 11. Two of these oncogenes, INT2 and HST1, both of which encode members of the fibroblast growth factor family, are implicated in the generation of virally induced mammary tumours in mice. Here we confirm earlier reports that the q13 region of chromosome 11, in which these genes are tandemly linked, is modestly amplified in approximately 15% of primary human breast cancers. This amplification is confined, with one exception, to cases in which the oestrogen receptor (ER) levels are in excess of 20 fmol/mg protein (P = 0.001). However, DNA amplification does not usually result in detectable expression of either the INT2 or HST1 gene. The data imply that some other gene in the vicinity must contribute to the development of a subset of ER-positive tumours and that assessing the amplification of this region of DNA may be of value in defining a separate category of ER-positive tumour.

Adult↗
PubMed1982

Immunological studies with human aortic elastin.

Antibodies to human fetal aortic elastin were isolated from sheep immunized with alpha-elastin peptides. In preliminary tests of specificity using passive hemagglutination, partial cross-reactivity was demonstrated with alpha-elastin from other species. However, in a double antibody radio-immunoassay alpha-elastin peptides from other mammalian species failed to compete with 125I-labelled human alpha elastin. These results suggest the existence of at least two different antigenic sites on the elastin molecule. One, a high affinity site, demonstrates species specificity at low antigen/antibody concentrations. The other, a low affinity site, is common to mammalian elastins and is demonstrated at high antibody/antigen concentrations. In the radioimmunoassay the antibodies showed considerably less avidity for adult human alpha-elastin than for the fetal antigen. This implies that the species specific site is age-dependent and probably involves the cross-linking region of the elastin molecule. Using the sheep antiserum immunohistochemical staining of elastic tissue has been developed. This should prove to be a useful technique for studying polymeric elastin in intact tissue by light microscopy and at the ultrastructural level.

Adult↗
PubMed1977

Automated urinary steroid profiles by capillary column gas-liquid chromatography and a computing integrator.

13 Urinary steroid metabolites have been determined by automated gas-liquid chromatography with a 20-m glass capillary column and a computing integrator. Concentrations up to 2 mg/24 h computed by the integrator compare well with those obtained by peak height measurements. At higher concentrations discrepancies occurred, paticularly for the C21 steroids where falsely low values were calculated using peak heights. Mean excretion by healthy males and females of seven steroid metabolities is presented.

Aged↗