Progesterone receptor variants associated with the PROGINS haplotype exhibit functional properties similar to those of wild-type progesterone receptor.
OBJECTIVE
The progesterone receptor (PR) is a ligand-activated transcription factor existing in two isoforms, A (PRA) and B (PRB), resulting from alternative promoter usage. It has long been speculated that genetic variants of PR are associated with the risk for various benign and malignant diseases, but data from clinical trials and in-vitro studies remain contradictory. The most extensively studied variant is termed PROGINS and consists of an intronic 320-bp Alu insertion and two coding (Ser344Thr, Val660Leu) and one silent single nucleotide polymorphism in complete linkage disequilibrium (allele frequency in Caucasians 9-19%). Our study aimed at elucidating the functional consequences of the PROGINS-associated single nucleotide polymorphisms of PRA and PRB (i.e. Thr344 and Leu660) as compared with wild-type PR (Ser344, Val660).


METHODS
The two PRA and two PRB full-length receptor variants were expressed by adenovirus in the PR-negative human breast cancer cell line T47D-Y and assayed with respect to transactivational properties, c-src activation, combined net mRNA and protein stability and hormone-binding characteristics.


RESULTS
In all experiments the wild-type PR and the PROGINS variant were undistinguishable.


CONCLUSIONS
Though there still might be tissue specific effects of the variants, our data indicate that these common PR variants do not functionally differ, which may provide a basis to explain the heterogeneous outcome of association studies.
Institute of Experimental and Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Martinistrasse, Hamburg, Germany. j.stenzig@uke.uni-hamburg.de
Justus
J
Stenzig
Andreas
A
Schweikert
Angelika
A
Piasecki
Grit
G
Höppner
Thomas
T
Eschenhagen
Thomas
T
Rau
D020087:Alu Elements / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D011110:Polymorphism, Genetic; D011374:Progesterone / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D055550:Protein Stability / Q000187:drug effects; D020871:RNA Stability / Q000187:drug effects; D011980:Receptors, Progesterone / Q000235:genetics* / Q000378:metabolism
D020033:Protein Isoforms; D011980:Receptors, Progesterone; D011374:Progesterone