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Hypomethylation of DNA in estrogen-induced and -dependent hamster kidney tumors
L J Lu1, J G Liehr, D A Sirbasku
1Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030.
Abstract:
The development and maintenance of DNA hypomethylation were investigated in male Syrian hamsters during the course of induction of renal carcinoma by estrogens and in an estrogen-dependent tumor derived from H-301 cells. The H-301 cell line was obtained from a primary renal carcinoma induced by E-diethylstilbestrol treatment. Covalent DNA modifications in estrogen-exposed kidney and tumor tissues were also examined. The five tumors investigated were induced by s.c. estrogen treatment of animals for 7-9 months. Covalent DNA adducts were detected in kidneys after 5-7 months of exposure to various estrogens, but not in primary tumors induced by estrogen treatment for 7-9 months. Estrogen-induced covalent DNA modifications likewise were not detectable in tumors grown in estrogenized hamsters inoculated with H-301 cells. In contrast, DNA was hypomethylated in primary tumors induced by E-diethylstilbestrol, estradiol or 11 beta-ethyl-17 alpha-ethinyl estradiol, but not in untreated and estrogen-exposed kidney. Compared with kidney tissue, there was an 11-24% decrease in total genomic DNA methylation in the estrogen-induced and -dependent tumors. DNA hypomethylation was maintained in tumors derived from H-301 cells. Discontinuation of estrogen treatment rapidly decreased the size of estrogen-dependent H-301 tumors, but did not affect the degree of DNA hypomethylation. Thus, DNA hypomethylation occurred in hormone-dependent primary neoplasms and was maintained after serial transplantations independent of the growth status.
Insights
Estrogen exposure can cause DNA hypomethylation in hamster kidney tumors, a change that persists even when tumors grow independently of the hormone. This DNA hypomethylation is a key feature of hormone-dependent cancers.
Area of Science:
- Oncology
- Epigenetics
- Carcinogenesis
Background:
- Estrogen exposure is linked to renal carcinoma development in Syrian hamsters.
- Hormone-dependent tumors exhibit distinct molecular alterations.
- Understanding epigenetic changes like DNA methylation is crucial for cancer research.
Purpose of the Study:
- To investigate DNA hypomethylation in estrogen-induced renal tumors and an estrogen-dependent cell line.
- To examine covalent DNA modifications in relation to estrogen exposure and tumor development.
- To determine if DNA hypomethylation is maintained in hormone-dependent tumors.
Main Methods:
- Induction of renal carcinoma in male Syrian hamsters using various estrogens.
- Establishment and use of an estrogen-dependent H-301 cell line.
- Analysis of DNA methylation levels and detection of covalent DNA adducts in kidney and tumor tissues.
Main Results:
- DNA hypomethylation was observed in estrogen-induced primary tumors and the H-301 cell line, showing an 11-24% decrease in genomic methylation.
- Covalent DNA adducts were detected in estrogen-exposed kidneys but not in primary tumors or H-301 tumors.
- DNA hypomethylation persisted in H-301 tumors even after discontinuation of estrogen treatment and tumor size reduction.
Conclusions:
- DNA hypomethylation is a characteristic feature of estrogen-dependent renal neoplasms in hamsters.
- This epigenetic alteration is maintained independently of tumor growth status and hormone dependency.
- The findings highlight the role of DNA hypomethylation in hormone-driven carcinogenesis.