Estradiol regulates tumor growth by influencing p53 and bcl-2 expression in human endometrial adenocarcinomas grown in nude mice.
This study analyzes the effects of estradiol on p53 and bcl-2 expression, tumor growth and cell kinetic parameters in three human endometrial adenocarcinomas grown in nude mice. The tumors used were estradiol receptor (ER) positive but differed in receptor concentration and hormone sensitivity. All three tumors expressed wild-type p53 protein. Using a tumor with an estradiol independent but responsive (inhibited) growth phenotype, we found that an increase in the circulating estradiol concentration led to increases in p53 expression and a decrease in bcl-2 levels, resulting in increased cell loss (CL) measured as delayed tumor growth. In another tumor which demonstrated estradiol independent and resistant growth, we observed an estradiol dose-related increase in p53 expression but no changes in bcl-2 expression or cell kinetic parameters. The ER mechanism of these cells was at least partly intact, as evidenced by maintained PgR induction. The third tumor showed an estradiol independent and resistant growth phenotype and a non-functional ER mechanism, lacking PgR induction. After estradiol treatment of the tumor-bearing animals no changes were observed in p53 or bcl-2 expression or in cell kinetics. We conclude that estradiol may regulate tumor growth in some ER positive human endometrial adenocarcinomas through regulation of p53 expression, which in turn regulates the bcl-2 protein concentration. Furthermore, this regulation of p53 expression is estradiol dose dependent. These growth regulating functions appear to be strongly influenced by ER mechanisms and do not seem to operate synchronously in tumors with an estradiol resistant growth phenotype.
Horvath
G
G
Division of Gynaecological Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden.
Leser
G
G
Karlsson
L
L
Delle
U
U
D000818:Animals; D004195:Disease Models, Animal; D016889:Endometrial Neoplasms / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011987:Receptors, Steroid / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D019253:Proto-Oncogene Proteins c-bcl-2; D011987:Receptors, Steroid; D016159:Tumor Suppressor Protein p53; D004958:Estradiol