Estrogen-induced tumorigenesis in the Copenhagen rat: disparate susceptibilities to development of prolactin-producing pituitary tumors and mammary carcinomas

Spady, Thomas J.; Harvell, Djuana M. E.; Snyder, Mary C.; Pennington, Karen L.; McComb, Rodney D.; Shull, James D.

doi:10.1016/s0304-3835(97)00455-2

Cited by 48 publications

(47 citation statements)

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confidence: 99%

“…Other rat strains including ACI, Wistar-Furth and Copenhagen have been reported to display estrogendependent growth and tumor induction. [9][10][11] On the other hand, the Brown-Norway, Holtzman and Sprague Dawley strains appear to be insensitive or resistant.7, 12) When susceptible strains were treated with E 2 , the size of the pituitary gland started to increase immediately and steadily expanded without any evident focal growth.9) The designation of tumor is given on the basis of the size of the gland and the abnormal appearance of the cells, which are highly correlated.13) Thus, the E 2 -induced weight increase in the gland well represents the E 2 -dependent tumorigenicity. The hypothalamus is not essential for the E 2 stimulation of pituitary growth, based on experiments involving transplantation of the pituitary gland.…”

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Strain Difference in Regulation of Pituitary Tumor Transforming Gene (PTTG) in Estrogen–induced Pituitary Tumorigenesis in Rats

Yin¹,

Fujimoto²,

Maruyama³

et al. 2001

Japanese Journal of Cancer Research

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Recently a novel oncogene, PTTG (pituitary tumor transforming gene) was isolated from a rat pituitary tumor cell line whose expression is apparently correlated with pituitary tumorigenesis. In the rat, estradiol (E 2 ) is known to induce anterior pituitary hyperplasia. The effects of E 2 , however, vary greatly among rat strains. Therefore we examined the expression of PTTG and its regulation by E 2 in F344, Wistar, Brown-Norway and Donryu rats. Four-week-old females were ovariectomized and a pellet containing 10 mg of E 2 was given s.c. Total RNA was isolated from the pituitary gland and PTTG mRNA was measured with a competitive RT-PCR technique. The F344 strain was the most susceptible to E 2 induction of pituitary tumorigenesis, followed by Wistar and BrownNorway, while no increase in pituitary weight was noted in Donryu rats. PTTG mRNA in the gland was induced by E 2 within 48-72 h in F344 and Wistar, but not in Brown-Norway or Donryu strains. These data suggest that PTTG expression may at least in part be responsible for strain differences in E 2 -induced pituitary tumorigenesis. Key words: Pituitary tumorigenesis -PTTG -Estrogen regulation -Strain difference -Competitive RT-PCRThe oncogene PTTG (pituitary tumor transforming gene) was first isolated from rat GH (growth hormone) tumor cell lines by differential mRNA display.1) Induction of PTTG alone results in transformation in NIH 3T3 cells, which become tumorigenic in vivo. Human PTTG was found to be expressed at only low levels in normal pituitary tissues but highly in secreting and non-secreting pituitary tumors as well as in a variety of tumor cell lines, including lung carcinoma, melanoma, leukemia, lymphoma and HeLa examples.2-4) More recent investigations have revealed that the gene is identical to securin, a sister chromatid separation inhibitor, whose overexpression may have an impact on cancer development by increasing genetic instability. 5)Chronic treatment of rats with estradiol (E 2 ) is known to result in the development of anterior pituitary tumors, which are initially benign masses and hormone-dependent, but may subsequently become autonomous. A study with F344 rats showed that PTTG mRNA in the pituitary gland increases in this process and that E 2 may regulate the expression.6) However, susceptibility to E 2 induction of pituitary tumors is highly strain-dependent. 7,8) The F344 strain is the most widely studied and the most sensitive to estrogen. Other rat strains including ACI, Wistar-Furth and Copenhagen have been reported to display estrogendependent growth and tumor induction. [9][10][11] On the other hand, the Brown-Norway, Holtzman and Sprague Dawley strains appear to be insensitive or resistant.7, 12) When susceptible strains were treated with E 2 , the size of the pituitary gland started to increase immediately and steadily expanded without any evident focal growth.9) The designation of tumor is given on the basis of the size of the gland and the abnormal appearance of the cells, which are highly correlated.13) Thus, the E 2 -ind...

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confidence: 99%

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confidence: 99%

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Strain Difference in Regulation of Pituitary Tumor Transforming Gene (PTTG) in Estrogen–induced Pituitary Tumorigenesis in Rats

Yin¹,

Fujimoto²,

Maruyama³

et al. 2001

Japanese Journal of Cancer Research

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“…The marker panel for QTL mapping consisted of simple se- (Shull et al 1997;Spady et al 1998a; quence length polymorphisms (SSLP) that were selected at ‫-02ف‬cM intervals from those distributed across the 20 autosomes 2000; Shull et al 2001;Gould et al 2004 1994). IM was performed hr dark conditions.…”

Section: Analysis Of Genotypesmentioning

confidence: 99%

“…ing 1945Holtzman et al 1979;Shull et al 1997; Average pituitary mass was increased 1.8-and 2.2-fold in et al. 1999c,d), Copenhagen (COP) (Spady et al 1998a, DES-treated (Holtzman ϫ F344)F 1 and (F344 ϫ Holtz1999d), and several other inbred rat strains (Noble et al man)F 1 rats, respectively, suggesting that sensitivity to 1940; Furth et al 1973;Spady et al 1999b). The grossly DES-induced pituitary growth is recessive or incompletely dominant in these crosses.…”

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Genetic Bases of Estrogen-Induced Pituitary Tumorigenesis

Strecker¹,

Spady²,

Schaffer

et al. 2005

Genetics

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Estrogens stimulate proliferation and enhance survival of the prolactin (PRL)-producing lactotroph of the anterior pituitary gland and induce development of PRL-producing pituitary tumors in certain inbred rat strains but not others. The goal of this study was to elucidate the genetic bases of estrogen-induced pituitary tumorigenesis in reciprocal intercrosses between the genetically related AC I and Copenhagen (COP) rat strains. Following 12 weeks of treatment with the synthetic estrogen diethylstilbestrol (DES), pituitary mass, an accurate surrogate marker of absolute lactotroph number, was increased 10.6-fold in AC I rats and 4.5-fold in COP rats. Composite interval mapping analyses of the phenotypically defined F 2 progeny from the reciprocal crosses identified six quantitative trait loci (QTL) that determine the pituitary growth response to DES. These loci reside on chromosome 6 [Estrogen-induced pituitary tumor (Ept)1], chromosome 3 (Ept2 and Ept6 ), chromosome 10 (Ept9 ), and chromosome 1 (Ept10 and Ept13). Together, these six Ept loci and one additional suggestive locus on chromosome 4 account for an estimated 40% of the phenotypic variance exhibited by the combined F 2 population, while 34% of the phenotypic variance was estimated to result from environmental factors. These data indicate that DES-induced pituitary mass behaves as a quantitative trait and provide information that will facilitate identification of genes that determine the tumorigenic response of the pituitary gland to estrogens.

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Dietary energy restriction abolishes development of prolactin-producing pituitary tumors in Fischer 344 rats treated with 17-βestradiol

et al. 1998

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Reduction in energy consumption is known to inhibit development of a variety of spontaneous, carcinogen-induced, and hormone-dependent cancers, but the mechanism or mechanisms by which this occurs remain unknown. We hypothesize that energy consumption may modulate development of estrogen-dependent neoplasms by altering the manner in which target cells respond to estrogens. To test this hypothesis, ovariectomized female Fischer 344 rats were fed diets that allowed consumption of different amounts of energy, and the ability of 17beta-estradiol (E2), administered for 10 wk from subcutaneous Silastic implants, to promote development of prolactin-producing pituitary tumors was examined. A 40% restriction of energy consumption virtually abolished the ability of E2 to promote development of pituitary tumors and associated hyperprolactinemia. A 25% restriction of energy consumption appeared to slightly inhibit E2-induced pituitary growth and hyperprolactinemia, but the observed degree of inhibition was not statistically significant. Interestingly, dietary energy restriction did not inhibit induction by E2 of pituitary cell proliferation and lactotroph hyperplasia. Furthermore, E2 treatment inhibited expression of testosterone-repressed prostate message-2 mRNA, a cellular marker of apoptosis, and this inhibitory effect of E2 was blocked by 40% energy restriction. These data suggest that dietary energy restriction virtually abolished E2-induced development of prolactin-producing pituitary tumors, not by blocking the ability of E2 to induce cell proliferation but rather by blocking the ability of E2 to enhance cell survival. This study and the accompanying paper provide the first indication that dietary energy consumption may modulate estrogen action at the level of the target cell.

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Estrogen-induced tumorigenesis in the Copenhagen rat: disparate susceptibilities to development of prolactin-producing pituitary tumors and mammary carcinomas

Cited by 48 publications

References 10 publications

Strain Difference in Regulation of Pituitary Tumor Transforming Gene (PTTG) in Estrogen–induced Pituitary Tumorigenesis in Rats

Strain Difference in Regulation of Pituitary Tumor Transforming Gene (PTTG) in Estrogen–induced Pituitary Tumorigenesis in Rats

Genetic Bases of Estrogen-Induced Pituitary Tumorigenesis

Dietary energy restriction abolishes development of prolactin-producing pituitary tumors in Fischer 344 rats treated with 17-βestradiol

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