Von Recklinghausen's disease with pheochromocytoma and nonmedullary thyroid cancer.
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Adrenal Gland Neoplasms↗
Biomedical subjects
B Sato
Publications and source records attributed to B Sato.
Stimulative effects of estrogens on tumor growth and 5 alpha-steroid production in a mouse Leydig cell tumor line (T 124958-R).
The effects of estrogens on the growth and enzyme activities for androgen synthesis in a mouse Leydig cell tumor line (T 124958-R) were studied. The s.c. implantation of a diethylstilbestrol pellet resulted in a marked enhancement of the tumor growth. 5 alpha-Reductase activity (nmol/g/h) in tumors rapidly grown in the presence of diethylstilbestrol pellet was 4 times higher than that in tumors slowly grown in the absence of diethylstilbestrol, whereas an inverse relation was found for 17 beta-hydroxysteroid oxidoreductase activity. 17-Hydroxylase activities were similar in both tumors. The major C21- and C19-steroids formed from progesterone by the tumors grown in the presence of estrogen were 5 alpha-steroids such as 3 alpha- or 3 beta-hydroxy-5 alpha-pregnan-20-one, 3 alpha, 17-dihydroxy-5 alpha-pregnan-20-one, androsterone, and 5 alpha-androstane-3 alpha, 17 beta-diol, whereas the major steroids formed by the tumors in the absence of estrogen were 4-ene-3-ketosteroids such as 20 alpha-hydroxy-4-pregnen-3-one, 17-hydroxy-4-pregnene-3,20-dione, and testosterone. Furthermore, 10(-8) M of 17 beta-estradiol added in serum-free medium for 10 days significantly enhanced 5 alpha-reductase activities per 10(6) cells but significantly inhibited 17 beta-hydroxysteroid oxidoreductase activity in primary cell culture. These results indicate that estrogens stimulate the growth of T 124958-R in vivo and that estrogens may directly enhance 5 alpha-reductase activity but inhibit 17 beta-hydroxysteroid oxidoreductase activity in T 124958-R cells.
17-Hydroxysteroid Dehydrogenases↗
Identification of immunoassayable estrogen receptor lacking hormone binding ability in tamoxifen-treated rat uterus.
Using two different monoclonal antibodies to human estrogen receptor (ER), the enzymeimmunoassay was performed. The values of ER contents in human breast cancer and untreated rat uteri obtained by this procedure were correlated well with those by [3H] estradiol binding assay. When estradiol was injected to immature rats, the enzymeimmunoassay showed the uterine receptor dynamic pattern similar to those analyzed by exchange assays. In contrast, tamoxifen administration induced the immunoassayable but nonsteroid binding form of ER. This ER-like antigen was the heat-labile molecule with the sedimentation constant of 7 S while ER in untreated rat uterine cytosol sedimented at 9 S. These results suggest the presence of unique molecular state of ER induced by tamoxifen.
Animals↗
Multiple estrogen binding sites in malignant mouse Leydig cells and their role in cell proliferation.
Incubation of dispersed cells derived from an estrogen-responsive mouse Leydig cell tumor with [3H]estradiol in the presence or absence of unlabeled estradiol showed the existence of two types of binding components with high (Kd approximately 10(-9) M) and low (Kd approximately 1.5 X 10(-8) M) affinity respectively. The use of unlabeled diethylstilbestrol as a competitor, however, abolished the low-affinity binder, resulting in the demonstration of the high binding site. This diethylstilbestrol-suppressible binding site was exclusively located in the nuclear fraction, even without hormonal stimuli. A long (5-hr) exposure of these cells to estrogen caused the decrease in the number of nuclear estrogen binding sites, which was similar to so-called 'processing' of putative nuclear estrogen receptor. The direct stimulative effect of estrogen on the proliferation of these cells was demonstrated by measuring cell numbers as well as thymidine incorporation into DNA in the cultured condition. These results would indicate that estrogen directly exerts its effects on this malignant Leydig cell through this unique nuclear binding site.
Animals↗
Mechanism of estrogen enhancement in the growth of androgen-dependent Shionogi carcinoma 115.
The mechanism of estrogen enhancement in the growth of androgen-dependent Shionogi carcinoma 115 (SC115) maintained in castrated DS mice by low doses of androgen (10 micrograms of testosterone propionate or 4 micrograms of 5 alpha-dihydrotestosterone/mouse/day) is reported. Although the low androgen treatment slightly but significantly (P less than 0.05) stimulated tumor growth, concomitant estrogen (4 micrograms of 17 beta-estradiol/mouse/day) significantly (P less than 0.01) enhanced the tumor growth. The high growth rate, histological type (medullary carcinoma), androgen dependency, and high androgen receptor content of the tumor grown during estrogen plus low androgen treatment did not differ significantly from those of the original SC115 tumor grown in normal males or in castrated mice treated with high doses of androgen. On the other hand, the treatment with low doses of androgen alone induced the development of slowly growing spindle-shaped cells from the medullary SC115 cells. The spindle-shaped cells containing low levels of androgen receptor were shown to be androgen independent and were also induced from the SC115 cells in nontreated castrated mice. These findings demonstrated that low doses of androgen and estrogen synergize to maintain and increase the growth of SC115 cells, whereas low doses of androgen alone fail to maintain the SC115 cells.
Androgens↗
Stimulative effect of physiological doses of androgen or pharmacological doses of estrogen on growth of Shionogi carcinoma 115 in mice.
It was generally accepted for 20 yr that the growth of Shionogi carcinoma 115 (SC115) is stimulated only by androgen. In the present study, the growth-stimulative effect of estrogen alone on SC115 tumors was examined in castrated mice. Daily injections of physiological doses of 17 beta-estradiol did not enhance the tumor growth. However, high doses of 17 beta-estradiol (10-100 micrograms/mouse/day) significantly stimulated the growth of tumors in a dose-dependent manner. Since high doses of diethylstilbestrol (10-50 micrograms/mouse/day), which does not bind to androgen receptor, could markedly stimulate the growth of tumors and since antiandrogen (cyproterone acetate) failed to inhibit the growth stimulation induced by high doses of 17 beta-estradiol, it is concluded that high doses of 17 beta-estradiol, which binds to androgen receptor with relatively low but significant affinity, enhance the tumor growth not via the androgen receptor system. The growth speed, histological type, content, and affinity of androgen, estrogen, and progesterone receptors and pattern of newly synthesized proteins labeled in vitro with [35S]methionine of tumors grown by high doses of estrogen were not significantly different from those of the original SC115 tumors grown in normal males. Furthermore, seed tumors from one to six generations grown by pharmacological doses of estrogen alone could rapidly grow only in normal males and not in castrated males. The present findings demonstrate that the growth of SC115 tumors in vivo is stimulated by physiological doses of androgen or pharmacological doses of estrogen.
Androgen Antagonists↗
Estrogen induces secretary proteins in transformed mouse Leydig cell in vivo, but not in vitro.
The estrogen-induced proteins were analyzed in one of estrogen responsive mouse Leydig tumors. The incubation of cells freshly prepared from solid tumors with [35S] methionine resulted in the demonstration of estrogen-induced secretary protein with a molecular weight of 34,000. The additional minor estrogen-induced secretary protein (36,000) was also identified. An exposure of these cells to the culture condition for 48 hr caused the loss of their ability to synthesize these secretary proteins even in the presence of estrogen. In contrast, minced tumor tissue was observed to sustain the ability to synthesize these proteins at least for 48 hr. These results would suggest that some cellular arrangement is required for the synthesis of estrogen-induced proteins.
Animals↗
Identification of unique macroamylase with abnormally low affinity for macromolecular substrate by short-chain amylose assay methods.
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Adult↗
Hormone receptor in renal cell carcinoma and correlation with clinical response to endocrine therapy.
Analyses of hormone receptors in cytosols from 41 renal cell carcinoma specimens were performed by the dextran-coated charcoal technique, using estradiol, synthetic progestin R5020 and synthetic androgen R1881. Binding data were calculated according to the method of Scatchard. Of 41 renal cell carcinomas estradiol receptor was detected in 11, R5020 receptor in 11 and R1881 receptor in 13. No significant correlation between histopathological findings and hormone receptors was observed. Patients were classified into those positive and negative for receptors. The clinical response of endocrine therapy for 17 with advanced residual or metastatic lesions after nephrectomy was studied in regard to the survival rates. Although there was no complete or partial regression in tumor size, the survival rate of patients with 1 or more receptors was significantly higher than that of patients negative for receptors (p less than 0.01). In conclusion, hormonal manipulation in patients with renal cell carcinoma cannot induce an antitumor effect but seems to increase survival in patients with receptors.
Adenocarcinoma↗
Partial characterization of protease(s) in human breast cancer cytosols that can degrade estrogen and progesterone receptors selectively.
Proteolytic activity in human breast cancer cytosols was studied using hormone receptors from rats as the substrates. Under the conditions tested, limited proteolysis of both the estrogen and the progesterone receptors in uterine cytosol was observed, but not proteolysis of the glucocorticoid or androgen receptors in liver or prostate cytosols, respectively. Although both the nonactivated and activated uterine estrogen receptors were attacked by the enzyme(s), molybdate-stabilized receptors were resistant to proteolysis. The product of estrogen receptor cleavage sedimented at approximately 4S in low-salt gradients and at 3 to 4S in high-salt gradients. This fragment retained both the steroid-binding and DNA-binding domains. The marked decrease in its DNA-binding ability, compared with the salt-dissociated but non-proteolyzed receptors, may be attributable to interactions of the fragment with dialyzable modulator(s) in cytosol. The proteolytic activity in tumor cytosol was leupeptin sensitive and was precipitated by (NH4)2SO4 at 30 to 60% saturation. Its sedimentation coefficient was 4 to 5S. The proteolytic activity was identified in 70% of estrogen receptor-negative tumors but in only 40% of estrogen receptor-positive tumors.
Breast Neoplasms↗
Effects of tamoxifen on estrogen-induced enhancement or inhibition of tumor growth in mouse Leydig cell tumor lines.
In order to avoid the complex dual effects of estrogen and antiestrogen, the attempt was made to establish the tumor lines in which estrogens show either stimulatory or inhibitory property in terms of the tumor growth. The administration of estrogen to host mice bearing one of the mouse Leydig cell tumor lines, called T 124958-R, resulted in marked enhancement of the tumor growth even at pharmacological levels of estrogen. On the other hand, estrogenization of host mice almost completely inhibited the growth of the other tumor line (T 22137) without detectable stimulatory effects. The physiocochemical properties of the cytosol estrogen receptor in both sublines were found to be similar in relation to the affinity toward ligands, steroid specificity, sedimentation profile, and the dissociation rate kinetics. Using these tumor lines, the action mechanism of tamoxifen on the tumor growth was examined. Daily administration of this compound (30 micrograms/mouse) led to enhanced tumor growth in T 124958-R, while the growth of T 22137 was inhibited by the same procedure. In the combination experiments, tamoxifen was found to be unable to antagonize estrogen-induced enhancement or inhibition of the growth in these tumors. In addition, both tumors contained similar levels of the antiestrogen binding sites. These results suggest that tamoxifen modulated the tumor growth through its estrogenic potency.
Animals↗
Growth-stimulative effect of estrogen on androgen-dependent Shionogi carcinoma 115.
The stimulative effect of 17 beta-estradiol on the growth of androgen-dependent Shionogi carcinoma 115 and estrogen receptor in the tumor were studied. The incorporation of 17 beta-[3H]estradiol following a single injection of 17 beta-[3H]estradiol into tumor-bearing animals was 5- to 20-fold higher in the tumor than in the spleen and blood. Scatchard plot analyses showed that the tumor cytosol possessed a 17 beta-estradiol-binding site having a high affinity for 17 beta-estradiol [Kd 1.1 +/- 0.1 nM (S.E.)]. Competition experiments demonstrated that the 17 beta-estradiol binding was specific only for estrogenic compounds. Using sedimentation coefficient obtained by high-salt sucrose gradient (4.0S) and Stokes radius obtained by gel chromatography on Sephadex G-200 (46 A), the molecular weight of 17 beta-estradiol-binding component in the tumor cytosol was estimated to be 76,400. In castrated DS mice, a slight but significant increase in growth of s.c. grafted tumors was found by daily s.c. injections of either 17 beta-estradiol or 10 micrograms per mouse of testosterone propionate. Growth of the tumor maintained by 10 micrograms of testosterone propionate was augmented markedly by the addition of 4 micrograms of 17 beta-estradiol, and the growth approached the level induced by 100 micrograms of testosterone propionate. Simultaneous injections of bromocryptine inhibited an increase in 17 beta-estradiol-induced prolactin secretion but had no effect on the 17 beta-estradiol-enhanced tumor growth. These results demonstrate for the first time the stimulative effect of estrogen on the growth of androgen-dependent Shionogi carcinoma 115. The tumor contains typical estrogen receptor, which might be able to transmit estrogen signal to tumor cell nuclei with regard to tumor growth.
Androgens↗
Chronic estrogen treatment causes an alteration in uterine estrogen receptor dynamics of rats.
Estrogen receptor content and dynamics in the uteri obtained from chronically estrogenized rats were analyzed. 12 day treatment with a subcutaneous implantation of a diethylstilbestrol pellet resulted in maximal stimulation of uteri with regard to wet tissue weight, DNA content, as well as progesterone receptor content without significant alteration of the estrogen receptor level. Estrogen receptor dynamics in just ovariectomized or ovariectomized and diethylstilbestrol-stimulated rats elicited by a single injection of estradiol were next examined using the exchange methods. The cytosol receptor content rapidly declined, with a small and temporary accumulation of the nuclear receptor in the uterus from rats continuously exposed to diethylstilbestrol during the preceding 12 days. A relatively rapid cytosol receptor replenishment was also observed in rats pretreated with diethylstilbestrol. This was accompanied by a rapid decrease in the nuclear receptor level to 70% of the preinjection value at 5 h after estradiol administration. These data are in contrast to findings on uteri of ovariectomized and nonestrogen-treated rats, in which a single injection of estradiol resulted in a prolonged nuclear receptor retention and a delayed cytosol receptor replenishment. Adrenalectomy did not result in a significant change of receptor dynamic patterns, suggesting that adrenal steroids do not play a role in the alteration of receptor dynamics elicited by continuous stimulation with diethylstilbestrol. These observations suggest that a continuous exposure of rat uteri to the estrogen causes an altered regulation of estrogen receptor dynamics by the homologous steroid compared to those in chronically estrogen-deprived rats.
Animals↗
[Regulatory mechanism of steroid receptors].
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Animals↗
Characterization of a unique nuclear estrogen-binding component in an estrogen-responsive mouse Leydig cell tumor.
An estrogen-responsive mouse Leydig cell tumor line (Tumor 124958) has been shown to contain only a low-affinity binder for estradiol in the cytosol fraction. This differed from the putative estrogen receptor in terms of its hormone-binding specificity as well as affinity. In addition, the possibility that an estrogen receptor-like molecule exists in the nuclei even without hormonal stimuli was examined using purified nuclei. Scatchard plot analyses showed that these nuclei possessed a large amount of estrogen binder having a high affinity for estradiol and diethylstilbestrol. The content of this nuclear binding component was not diminished by using molybdate, a potent inhibitor for receptor activation, and in vitro incubation of collagenase-dispersed cells with estradiol did not cause significant increase in the number of nuclear binding sites when compared with the values obtained by direct incubation of isolated nuclei with estradiol. These results support the view that this nuclear estrogen binder is not due to artificial migration of the cytosol receptor into nuclei during homogenization. The characterization of this nuclear binding component under cell-free conditions revealed that its affinity for estradiol in Mg2+-containing buffer was temperature dependent (Kd 3 nM at 30 degrees and 12 nM at 0 degrees) without significant alteration in the number of maximum binding sites. Introduction of a chelating agent (ethylenediaminetetraacetate) into the buffer system abolished the temperature effect on the affinity, resulting in high affinity for estradiol at both low and high temperatures. These Mg2+ and temperature effects were reversible. In addition, when compared with putative nuclear estrogen receptors, this nuclear binding was observed to be relatively resistant to high salt or micrococcal nuclease treatments in relation to solubilization from nuclei. However, trypsin digestion was found to result in a marked decrease in the nuclear binding sites, indicating that this unique nuclear binding component contains a protein unit(s). These results suggest the possibility that this tumor line contains a unique unoccupied nuclear estrogen binder which might be able to transmit estrogen signals to tumor cell nuclei with regard to tumor growth.
Animals↗
[Heterogenous action mechanisms in steroid hormone-responsive cancer and their effects on tumor growth].
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Animals↗
Steroid receptor forms and their interaction with cytoplasmic modulators.
The cytoplasmic modulator affecting steroid receptor functions was studied. The diminution in the concentration of the low molecular weight substances in the cytosol caused the increased interaction of hormone-receptor complexes with nuclei (a step termed activation). Furthermore, dialysis of rat uterine cytosol in the absence of estrogens subsequently followed by incubation with isolated nuclei resulted in the demonstration of an appearance of unoccupied nuclear receptor which was found to be 4S form. The addition of the dialyzable compound into rat uterine estrogen receptor system caused the suppression of temperature-dependent activation while the already-activated estrogen receptor was not affected by the small molecules in relation to its nuclear binding ability. These results may indicate that this small molecule, so-called the low molecular weight inhibitor, is capable of interacting with nonactivated receptor. In one of the estrogen-independent Leydig cell tumor lines, unique low-affinity estrogen binder with a mol. wt approximately 36,000 was identified. This binder did not show appreciable nuclear binding ability even after conventional heat activation. However, removal of the small molecules from this cytosol resulted in a marked increase in affinity for estrogens with a concomittant alteration of the mol. wt to approximately 70,000. These changes also paralleled a dramatic enhancement of nuclear binding ability. This small molecule might be different from the low molecular weight inhibitor suppressing receptor activation, since this tumor cytosol containing unique estrogen binder had much less inhibitory activity against receptor activation when compared with those in the other cytosol containing usual estrogen receptor systems. In adult rat urine cytosol, a new modulator was identified to recognize only activated estrogen receptor but not glucocorticoid receptor and to induce receptor aggregation with a concomittant loss of its nuclear binding ability. These reactions were accelerated by the presence of physiological or higher KCl concentration and exposure to a relatively high temperature (20-30 degrees C). Interestingly, this factor was not identified in the immature rat uteri or liver.
Adrenalectomy↗
5 beta- and 5 alpha-reductases for 4-ene-3-ketosteroids in golden hamster ovaries at different stages of development.
Ovarian homogenates from 10-, 23- 128- and 60-day-old golden hamsters were incubated with [14C]-4-androstene-3,17-dione or [7-3H]-progesterone in the presence of NADPH and enzyme activities and metabolism of progesterone were estimated. A rapid increase in uterine weight was found around 28 days of age. The activity of 5 alpha-reductase was very high in the ovaries of 23-day-old hamsters (647 +/- 117 (SD) nmol/g tissue/h), high in those of 28-day-old hamsters (135 +/- 4) and low in those of 10- and 60-day-old animals (20 +/- 16, 39 +/- 11). However, the activity of 5 beta-reductase was high in all ovaries of golden hamsters at different stages of development (84-132 nmol/g tissue/h). The major C-21-17-hydroxysteroids and C19-steroids formed from progesterone by the ovaries of 23-day-old hamsters were 5 alpha-steroids such as 3 alpha, 17-dihydroxy-5 alpha-pregnan-20-one and androsterone, whereas those by the ovaries of 28- and 60-day-old hamsters were 4-ene-3-ketosteroids and 5 beta- and 5 alpha-steroids such as 17-hydroxy-4-pregnene-3,20-dione. 3 alpha, 17-dihydroxy-5 alpha- and 5 beta-pregnan-20-one, 4-androstene-3,17-dione, testosterone and androsterone. The formation of oestradiol-17 beta and oestrone from progesterone was found only in the ovaries of 38- and 60-day-old hamsters. These results show that similarly high levels of 5 beta-reductase are present in all ovaries from suckling, immature and adult golden hamsters and that high levels of 5 alpha-reductase are formed only in ovaries from immature hamsters, especially those with small uterus. The active 5 alpha-reduction of 4-ene-3-ketosteroids may be responsible for the decrease in the formation of oestrogens in immature hamster ovaries.
3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗