Estrogen-Dependent Kidney Tumors

Liehr, Joachim G.; Sirbasku, David A.

doi:10.1007/978-1-4684-4814-6_11

Cited by 10 publications

(2 citation statements)

References 38 publications

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“…In studies of mechanisms of hormonal carcinogenesis, natural hormones, such as E2, as well as synthetic estrogens, such as diethylstilbestrol, have been shown to induce tumors in rodent models [6][7][8]. However, the mechanisms of estrogen-induced carcinogenesis have not yet been fully characterized [7,9], though the estrogen-induced hamster kidney and the estrogen-induced rat mammary tumor models have provided a degree of understanding of the mechanism of human mammary carcinogenesis through shared biochemical and molecular characteristics [7][8][9][10][11][12][13]. In principle, however, the potential of an estrogen to initiate estrogen-estrogen receptor mediated pathways does not always correlate with its carcinogenic potential in rodent models [7,[14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Suppression of calbindin D28K in estrogen-induced hamster renal tumors

Bhat

Epelboym

2004

The Journal of Steroid Biochemistry and Molecular Biology

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Section: Introductionmentioning

confidence: 99%

Suppression of calbindin D28K in estrogen-induced hamster renal tumors

Bhat

Epelboym

2004

The Journal of Steroid Biochemistry and Molecular Biology

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“…In the present study, experiments were carried out to search for adduct formation in an established animal model for estrogen-induced cancer-i.e., the induction of renal carcinoma in the Syrian hamster (24). This model was chosen because a large number of natural and synthetic estrogens of diverse structure are known to induce renal carcinoma in 80-100%o ofthe animals within 6-9 months after s.c. estrogen implantation (25). The tumors formed are malignant, as shown by their invasiveness and ability to metastasize and to kill the host; they are initially estrogen-dependent but acquire autonomy after serial transplantations (24, 26).…”

Section: Introductionmentioning

confidence: 99%

Estrogen-induced endogenous DNA adduction: possible mechanism of hormonal cancer.

Liehr¹,

Avitts²,

Randerath³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

123

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In animals and humans, estrogens are able to induce cancer in susceptible target organs, but the mechanism(s) of estrogen-induced carcinogenesis has not been elucidated. A well-known animal model is the development of renal carcinoma in estrogen-treated Syrian hamsters. Previous work demonstrated the presence of covalent DNA addition products (adducts) in premalignant kidneys of hamsters exposed to the synthetic estrogen, diethylstilbestrol, a known human carcinogen. In the present study, the natural hormone, 178-estradiol, and several synthetic steroid and stilbene estrogens were examined by a 32P-postlabeling assay for their capacity to cause covalent DNA alterations in hamster kidney. Chronic exposure to each of the estrogens tested led to the gradual formation of five chromatographically distinct unusual nucleotides specifically in kidney DNA. Irrespective of the estrogen used, chromatograms exhibited identical mobilities of each of these adducts in seven different systems on PEI-cellulose anionexchange TLC, in three different conditions on reversed-phase TLC, and in one system on silica gel partition TLC. Therefore, the DNA adducts observed did not contain moieties derived from the structurally diverse estrogens. It is concluded that each of the estrogens induced the binding of the same unknown endogenous compound (or compounds) to target tissue DNA. This novel property of estrogens is postulated to play a key role in hormone-induced malignancy.The formation of covalent DNA addition products (adducts) is generally accepted as a key feature of the initiation of carcinogenesis by "genotoxic" chemicals-chemicals that are able to damage genetic material (1, 2). Unless the modified DNA nucleotides are promptly repaired, miscoding may ensue upon DNA replication, leading to point mutations, activation of oncogenes, and chromosomal alterations (3). A number of short-term tests have been developed recently to detect genotoxic activity of chemicals (4-6). Also, DNA adduct formation has been shown in vivo in experimental animal test systems with many chemical carcinogens of diverse structure (1, 2, 7). However, a number of important carcinogens (8) exist that do not fit this description and therefore have been classified as nongenotoxic carcinogens (9). While their mechanism of action has not as yet been defined, some of them [such as estrogens (10-13) and the environmental pollutant 2, 3,7,8-tetrachlorodibenzo-p-dioxin (14, 15)] have been shown to promote transformation-i.e., they facilitate the expression of neoplastic properties of previously initiated susceptible cells. Estrogens were found to be negative in short-term assays for the induction of gene mutations, irrespective of whether this was measured in prokaryotic (16,17) or eukaryotic (18,39) A central question to be addressed in this context is whether or not estrogens, like the majority of chemical carcinogens, induce covalent DNA alterations in the target tissue of carcinogenesis in vivo. In the present study, experiments were carried out to searc...

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Differential regulation of c-fos expression in estrogen-induced hamster renal tumors compared with kidney not due to creation of an estrogen-response element by point mutation in the gene's flanking sequence

Sarabia

Liehr

1999

Mol. Carcinog.

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The conversion of a palindromic sequence, GGTCTnnnAGACC, in the 5'-flanking region of the murine c-fos proto-oncogene into a functional estrogen-response element by a single base change into GGTC(A/G)nnnAGACC has previously been postulated [Nawaz et al., 1993] as a possible mechanism of the induction of tumors by estrogens. This attractive hypothesis has been investigated in estradiol-induced Syrian hamster kidneytumors, in H-301 kidney tumor cells (a cell line derived from the Syrian hamster tumor), and in normal kidney tissue. The c-fos gene is differentially regulated by a classical estrogen receptor-mediated process in tumors, whereas in the acutely treated kidney, estradiol induces c-fos expression independent of estrogen-receptor function. In this study, we identified in the 5'-flanking region of the hamster kidney c-fos gene the sequence AGTCCnnnAGACC, which closely resembled but did not appear to function as an estrogen-response element. No mutations were detected in this sequence or in the 5'-flanking region of c-fos genes from three different primary tumors and from H-301 tumor cells. To rule out the possibility of a low copy number of mutant alleles in a tumor sample, polymerase chain reaction-based single-strand conformation polymorphism analysis was performed on 372 base pairs of the 5'-flank of the c-fos gene (-367 to +5 base pairs relative to the transcription start point). Nine different kidney tumor DNA samples and five normal kidney tissue samples (controls) produced an identical pattern of DNA bands, suggesting a lack of natural polymorphisms and mutations in this region of the c-fos gene. Acute treatment of hamsters with 17beta-estradiol for 6 h significantly induced renal c-fos mRNA expression, whereas control levels of c-fos were restored by co-treatment with estradiol and either N-acetyl-L-cysteine or alpha-naphthoflavone. We concluded that the previously observed change in regulatory control of c-fos expression in kidney versus estradiol-induced tumors does not involve the creation of a functional estrogen-response element by single point mutation in the 5'-flanking region of the gene. Additionally, c-fos expression in estradiol-treated hamster kidneys appears to be mediated by free radicals generated by the catechol metabolites of estradiol and not by the activation of any estrogen receptor.

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Estrogen-Dependent Kidney Tumors

Cited by 10 publications

References 38 publications

Suppression of calbindin D28K in estrogen-induced hamster renal tumors

Suppression of calbindin D28K in estrogen-induced hamster renal tumors

Estrogen-induced endogenous DNA adduction: possible mechanism of hormonal cancer.

Differential regulation of c-fos expression in estrogen-induced hamster renal tumors compared with kidney not due to creation of an estrogen-response element by point mutation in the gene's flanking sequence

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