Untersuchung zur Assoziation des Wachstumshormon-Rezeptor-Deletion-Exon 3(GHRd3)-Polymorphismus mit dem Auftreten von Brustkrebs

Der in der Bevölkerung mit einer Allelfrequenz von 25-32% vorkommende Wachstumshormonrezeptor-Deletion-Exon 3-linebreak Polymorphismus (GHRd3) verfügt im Vergleich zur normalen Rezeptorform mit Expression von Exon 3 (GHRfl) über eine erhöhte Bioaktivität. Die Tatsache, dass Wachstumshormon sowie Wac...

Full description

Saved in:
Bibliographic Details
Main Author: Bub, Melanie Christiane
Contributors: Kann, P.H. (Prof. Dr. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2013
Online Access:PDF Full Text
Tags: Add Tag
No Tags, Be the first to tag this record!

The human growth hormone receptor (GHR) plays in important role in the GH signaling cascade. Two of the most common isoforms of GHR are derived from retention (GHRfl) or from deletion (GHRd3) of exon 3. GHRd3 is associated with a higher receptor activity and a higher responsiveness to GH although the molecular mechanisms are not completely explained. GH as well as GHR are locally producted in the mammary gland acting there in an autocrine/paracrine manner. The gene expression of both GH and GHR are increased in breast cancer tissue. The GHRd3-isoform might have a growth supporting effect in breast tissue due increased receptor function and thus contribute to the development of breast cancer. Therefore the aim of the study was to investigate a potential association between GHRd3 with the development of breast cancer. 125 woman with breast cancer and 125 controls without any previous malignant disease and without familial breast cancer were recruited. The GHRd3 polymorphism was genotyped by performing a Light Cyclertexttrademark PCR and subsequent melting curve analysis. IGF-1 serum concentrations were measured by AMP-IGF-I-ELISA and analysed by GHRd3/fl genotypes. Clinical data as age, age of onset in case of breast cancer, smoking behavior, using of oral contraceptives or hormone replacement therapy were collected by questionnaire. The GHRd3 allele frequency was 30,4% in cases and 28% in controls. The odds ratio (OR) of breast cancer was 1,066 (95% CI 0,649-1,75; p=0,80) for patients carrying at least one GHRd3 allele compared with patients carrying just GHRfl. IGF-1 serum concentrations did not differ between cases and controls (p=0,26) neither between patients carrying one or two GHRd3-allels compared with patients with the full-length receptor (p=0.50). Cases and controls showed no statistical differences in BMI (P=0,4) nor in the use of hormone-replacement therapy (p=0,41) but in mean age (p<0,001) body height (p=0,009), weight (p=0,019), consumed pack years (p=0,035) and in the use of hormonal contraception (p<0,001). Age of disease onset did not differ between GHRd3-allele carriers and noncarriers (p=0.53). No significant association was found between GHRd3 polymorphism and breast cancer. The GHRd3 allele was not associate with a younger age of disease onset but the number of homozygous GHRd3 allele carriers was very low in this study so further studies with a greater study population are required to confirm these results. Interestingly a positive association between body length and breast cancer was found which leads to new questions how the somatotropic axis which influences body length in children as well as in adults is connected to the development of malignant diseases.