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Estrogen-induced microsatellite DNA alterations are associated with Syrian hamster kidney tumorigenesis
A V Hodgson1, S Ayala-Torres, E B Thompson
1Stehlin Foundation for Cancer Research, Houston, TX 77003-5802, USA.
Abstract:
Exposure to estrogens is associated with an increase in cancers, including malignancies of the breast and uterus in humans, and of the kidney in hamsters. DNA damage induced by metabolic activation of estrogen has been postulated to result in gene mutations critical for the development of estrogen-induced kidney tumors in hamsters. As part of our examination of the genetic consequences of estrogen-induced DNA damage, we searched for estrogen-induced alterations in microsatellite DNA, a frequent site of mutation in tumors. Genomic DNA isolated from kidney of hamsters treated with estradiol, from estrogen-induced kidney tumors and from untreated age-matched controls, was examined by Southern blot analysis with three multi-locus oligonucleotide probes: (GACA)4, (CAC)6 and (CAG)6. Alterations in DNA fragments containing GACA and CAC tandem repeats were detected in kidney DNA of hamsters treated with hormone for 3 and 4 months, whereas no such effects were seen in control animals. In estrogen-induced tumors, microsatellite alterations were observed in fragments that contain these same two repeat sequences and also CAG repeat sequences. The induction of microsatellite alterations by estradiol in kidney DNA preceding estrogen-induced renal malignancy may play a role in hormone-induced tumorigenesis.
Insights
Estrogen exposure can cause kidney tumors in hamsters. This study found that estradiol causes changes in microsatellite DNA, suggesting a role for these genetic alterations in hormone-induced cancer development.
Area of Science:
- Oncology
- Genetics
- Endocrinology
Background:
- Estrogen exposure is linked to increased cancer risk, including human breast and uterine cancers, and hamster kidney tumors.
- Metabolic activation of estrogen is hypothesized to cause DNA damage, leading to mutations crucial for estrogen-induced kidney tumor development.
Purpose of the Study:
- To investigate estrogen-induced DNA damage by examining alterations in microsatellite DNA, a common mutation site in tumors.
- To explore the role of microsatellite DNA alterations in the development of estrogen-induced kidney tumors in hamsters.
Main Methods:
- Genomic DNA was isolated from the kidneys of estradiol-treated hamsters, estrogen-induced kidney tumors, and control hamsters.
- Southern blot analysis was performed using three multi-locus oligonucleotide probes: (GACA)4, (CAC)6, and (CAG)6.
Main Results:
- Alterations in DNA fragments with GACA and CAC tandem repeats were detected in the kidney DNA of hamsters treated with estradiol for 3 and 4 months.
- No microsatellite alterations were observed in control animals.
- Estrogen-induced tumors exhibited microsatellite alterations in fragments containing GACA, CAC, and CAG repeat sequences.
Conclusions:
- Estradiol induces microsatellite alterations in kidney DNA prior to the development of renal malignancy.
- These microsatellite alterations may play a significant role in hormone-induced tumorigenesis.