Related Experiment Videos
Estrogen-induced proto-oncogene and suppressor gene expression in the hamster kidney: significance for estrogen
1Division of Etiology and Prevention of Hormonal Cancers, Kansas Cancer Institute, University of Kansas Medical Center, Kansas City 66160-7412, USA.
Abstract:
Chronic administration of estrogen to male Syrian hamsters for 7.0 to 9.0 months induces a high frequency of estrogen-dependent renal cancers. We have proposed a sequential multistage scheme involving tubular cell damage, regenerative cell proliferation, aneuploidy, chromosomal imbalance, genetic instability, gene alteration, and amplification as essential steps for estrogen carcinogenesis in this model. A systematic study was undertaken to assess the expression of nuclear proto-oncogenes, c-myc, c-fos, and c-jun, and suppressor genes, p53 and WT-1, by Northern blot analysis to further support this scheme. Hamster kidney RNA, taken at monthly intervals (1.0 to 6.0 months) from diethylstilbestrol (DES)-treated castrated male hamsters and corresponding age-matched untreated controls was used in these studies, as well as primary estrogen-induced renal tumor RNA, for reference. Although no significant changes in the expression of these proto-oncogenes were detected in the first 4 months of estrogen treatment relative to age-matched controls, 2.1-kb c-myc expression was elevated 2.8- and 4.1-fold at 5.0 and 6.0 months, respectively. Moreover, the expression of 2.2-kb c-fos transcript rose 4.6- and 4.8-fold; and 3.2- and 2.7-kb c-jun expression increased 2.8- and 5.1-fold at these same respective estrogen treatment time intervals. Tumor suppressor gene expression, p53 and WT-1, was also evaluated in similar estrogen-exposed hamsters. Although no significant changes were found in hamster kidney p53 expression in the first 5.0 months of DES treatment, it rose 1.8-fold at 6.0 months of estrogen treatment and more than 2.0-fold in the primary renal tumor. In contrast, no detectable changes in WT-1 expression were found during the first 6.0 months of DES treatment. However, a dramatic 7.0-fold increase in WT-1 expression was observed in the primary renal tumor. It is evident that two WT-1 transcripts reside in the hamster kidney; a lower molecular weight transcript was found in the normal adult kidney, and a higher molecular weight 3.2-kb transcript was observed in the renal tumor, similar to that seen in the newborn mouse kidney. In summary, the estrogen-induced inappropriate gene expression, including p53, reported herein, is consistent with the view that the elevations seen in gene expression contribute to proliferative advantages of certain proximal tubular interstitial cells necessary for estrogen-driven tumor formation in the hamster.
Insights
Chronic estrogen exposure in male hamsters causes kidney cancer by altering gene expression. Proto-oncogenes like c-myc and c-fos, and tumor suppressor genes p53 and WT-1, show significant changes, particularly in later stages and tumors.
Area of Science:
- Oncology
- Molecular Biology
- Carcinogenesis
Background:
- Chronic estrogen administration in male Syrian hamsters is a known model for inducing renal cancers.
- A multistage carcinogenesis scheme involving genetic alterations has been proposed for this model.
- Understanding gene expression changes is crucial for elucidating estrogen-driven tumor formation.
Purpose of the Study:
- To investigate the expression patterns of key nuclear proto-oncogenes (c-myc, c-fos, c-jun) and tumor suppressor genes (p53, WT-1) during estrogen-induced renal carcinogenesis in male Syrian hamsters.
- To provide molecular evidence supporting the proposed multistage scheme of estrogen carcinogenesis.
- To correlate gene expression changes with specific time points of estrogen exposure and tumor development.
Main Methods:
- Northern blot analysis was used to assess gene expression.
- Hamster kidney RNA was collected monthly over 6 months from diethylstilbestrol (DES)-treated castrated males and age-matched controls.
- RNA from primary estrogen-induced renal tumors was also analyzed for comparison.
Main Results:
- Proto-oncogene expression (c-myc, c-fos, c-jun) showed significant increases at 5 and 6 months of estrogen treatment.
- p53 tumor suppressor gene expression increased at 6 months and in tumors.
- WT-1 tumor suppressor gene expression remained unchanged during treatment but dramatically increased in renal tumors, with a distinct higher molecular weight transcript observed.
Conclusions:
- Estrogen-induced renal carcinogenesis in hamsters involves significant alterations in the expression of proto-oncogenes and tumor suppressor genes.
- Elevated gene expression, including p53 and WT-1, likely contributes to the proliferative advantage of renal cells, driving tumor formation.
- The distinct WT-1 transcript in tumors suggests a specific role in advanced stages of estrogen-driven renal cancer.