UMLS:C0006142 - FACTA Search

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Query: UMLS:C0006142 (breast cancer)
160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inhibition of estrogen production provides effective therapy for patients with hormone-dependent breast cancer. The source of estrogens in premenopausal women is predominantly the ovary, but after the menopause, estradiol is synthesized in peripheral tissues through the aromatization of androgens to estrogens. Uptake from plasma is the primary mechanism for maintenance of estradiol concentrations in breast cancer tissue in premenopausal women, whereas several steps may be operant in postmenopausal women. These include enzymatic synthesis of estradiol via sulfatase, aromatase, and 17 beta-hydroxysteroid dehydrogenase in the tumor itself. Aromatization of androgens secreted by the adrenal to estrogens in peripheral tissues and transport to the tumor via circulation in the plasma provides another means of maintaining breast tumor estradiol levels in postmenopausal women. These various sources contribute to the high tissue estrogen levels measured in breast tumor tissue. To effectively suppress tissue concentrations of estrogens and circulating estradiol in postmenopausal patients, various aromatase inhibitors have been developed recently. These include steroidal inhibitors such as 4-hydroxy-androstenedione as well as non-steroidal compounds with imidazole and triazole structures. The most potent of these, CGS 20267, is reported to suppress levels of active estrogens (i.e., estrone, estrone sulfatase, and estradiol) by more than 95%. This compound can suppress both serum and 24-hr urine estrogens to a greater extent than produced by the second generation inhibitor, CGS 16949A. CGS 20267 is highly specific since it does not affect cortisol and aldosterone serum levels during ACTH stimulation tests nor sodium and potassium balance in 24-hr urine samples.(ABSTRACT TRUNCATED AT 250 WORDS)
Breast Cancer Res Treat 1995
PMID:Aromatase inhibitor development for treatment of breast cancer. 774 29

Recently, compounds having pure antiestrogenic activity have become available. In this study, we examined the activity of the new steroidal antiestrogen EM-170 (N-n-butyl, N-methyl-11-(16' alpha-chloro-3',17' alpha-dihydroxy-estra-1',3',5'-(10')-trien-7' alpha-yl) undecanamide) on the growth of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma stimulated by treatment with estrone (E1), a steroid known to play an important role as precursor of 17 beta-estradiol (E2), especially in postmenopausal women. Twenty-five days after ovariectomy (OVX), tumor volume in control OVX animals decreased to 51.4 +/- 11% of the initial volume; treatment with E1, administered by Silastic implants, stimulated tumor growth to 179 +/- 21%. Treatment with the antiestrogen EM-170 at a dose of 200 micrograms (twice daily) not only completely reversed the stimulatory effect of E1, but also inhibited tumor growth to 30.5 +/- 9.6%, an effect that is 41% (P < 0.01 vs OVX control) greater than that of ovariectomy alone. At a relatively low dose of 40 micrograms (twice daily), 20 days of treatment with EM-170 reversed by 55% the stimulatory effect of E1 (1.0 micrograms, subcutaneously, twice daily) on tumor growth in OVX animals. On the other hand, the antiestrogen also induced a significant inhibitory effect on 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) activity in the DMBA-induced mammary tumors, an effect that is in agreement with the marked reduction caused by the same treatment on tumor estradiol (E2) levels in E1-treated OVX animals.(ABSTRACT TRUNCATED AT 250 WORDS)
Breast Cancer Res Treat 1995 Mar
PMID:Inhibitory effect of a steroidal antiestrogen (EM-170) on estrone-stimulated growth of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma in the rat. 774 51

The growth of the mammary gland during the active genital period depends on a delicate balance between the action of the two major female sex steroid hormones, estradiol and progesterone. The regulation of growth and maturation of the gland primarily depends on the combined action of estradiol and progesterone. Breast epithelial proliferation is maximal during the luteal phase of the menstrual cycle. While estrogen appears to be the major impetus to the proliferation of mammary cells, the effect of progestin is subject to debate. Progestins have either a positive, modest or no growth effect or may even inhibit growth. Progestins could stimulate the development of malignant cells in contrast to normal or non-malignant cells. It is difficult to extrapolate in vitro results to the human breast. There is presently no direct evidence that progestins regulate the concentration of estrogen receptors (ER) in normal breasts. Furthermore, it is possible that each type of progestin may have different effects. Most studies suggest that progestins are effective in the treatment of premenstrual syndrome and benign breast disease. The therapeutic basis for the use of progestins is the suppression of pituitary-ovarian function the reduction of the effect of estrogen on breast tissues. Whether progestins give protection against breast cancer is less clear. If they do, the mechanism is not the same as that of the endometrium [down-regulation of ER, increase of 17 beta-hydroxysteroid dehydrogenase activity (E2DH)]. High doses of oral synthetic progestins are effective in the treatment of breast cancer.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Effects of progesterone and progestational hormones on the mammary gland]. 779 24

EDH17B2, the gene encoding 17 beta-hydroxysteroid dehydrogenase type 1, has been suggested as a candidate for the familial breast cancer gene, BRCA1, located on 17q12-q21. We analyzed the promoter region of EDH17B2 in DNA from 20 control individuals and 40 patients with familial breast cancer. Two frequent (designated vI and vIII) and two rare (vII and vIV) nucleotide variations were present in both the breast cancer patients and the controls, except the alteration vII, which was found only in one patient. Although the data do not support the identification of EDH17B2 as the BRCA1 gene, it is of interest that point mutation vIV (A-->C) was located in the putative TATA box of the EDH17B2 gene. Reporter gene analyses showed that the mutation vIV decreases EDH17B2 promoter activity by an average of 45% in in vitro assays, suggesting that nucleotide A at position -27 is significant for efficient transcription.
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PMID:A point mutation in the putative TATA box, detected in nondiseased individuals and patients with hereditary breast cancer, decreases promoter activity of the 17 beta-hydroxysteroid dehydrogenase type 1 gene 2 (EDH17B2) in vitro. 782 82

The synthesis of a 16 alpha-(bromoalkylamide) derivative of estradiol (N-butyl, N-methyl, 11-[3',17' beta-(dihydroxy)-1',3',5' (10')-estratrien-16' alpha-yl]-9(R/S)-bromo undecanamide) was performed by two different approaches starting from estrone. Each approach has the same key intermediate, containing an aldehyde group, but differs by the bromination step and the timing of formation of the amide group. This compound was found to cause, at 100 microM, a complete inhibition of 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) responsible for the interconversion of estrone and estradiol. The corresponding IC50 value was 10.6 microM. In the estrogen-sensitive ZR-75-1 human breast cancer cell line, this estradiol derivative has no estrogenic activity at 30 nM and only a minimal estrogenic activity (10% above the basal level) at 1 microM. At this latter concentration, this compound causes a 28% inhibition of 0.1 nM E2-induced cell proliferation (antiestrogenic activity). Thus, the introduction of a side-chain with a secondary bromide and a butyl methyl amide group at the 16 alpha-position of estradiol has two interesting effects; namely an inhibition of cytosolic 17 beta-HSD and a blockade of the estrogenic effect of estradiol.
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PMID:N-butyl, N-methyl, 11-[3',17' beta-(dihydroxy)-1',3',5'(10')-estratrien-16' alpha-yl]-9(R/S)-bromo undecanamide: synthesis and 17 beta-HSD inhibiting, estrogenic and antiestrogenic activities. 784 36

Oestradiol 17 beta-hydroxysteroid dehydrogenase (E2DH) has a pivotal role in the regulation of oestradiol (E2) concentrations in normal and malignant breast tissues. Previous studies have suggested that a number of cytokines can stimulate E2DH activity to increase the conversion of oestrone (E1) to E2. In this investigation we have examined the effect of TNF alpha, interleukin-1 beta (IL-1 beta) and IL-6 on E2DH activity in MCF-7 breast cancer cells. These cytokines may be produced by breast tumours and their presence in conditioned medium (CM) from tumour-derived fibroblasts was also measured to assess their possible contribution to its E2DH stimulatory activity. Treatment of MCF-7 cells with IL-1 beta and TNF alpha (5 ng/ml) significantly increased (P < 0.001) reductive E2DH (red-E2DH, the conversion of E1 to E2) activity. In contrast, IL-6 at a concentration of 100 ng/ml produced little, if any, stimulation of reductive activity. Combinations of all three cytokines acted synergistically to stimulate red-E2DH activity. No cytokine, either alone or in combination, affected oxidative (E2-->E1) activity. Significant concentrations of IL-6 and IL-1 beta were detected in CM, but the stimulation of red-E2DH activity was much greater than that which could be explained by their levels alone. It is concluded that these cytokines may play an important role in regulating E2DH activity in breast cancer cells and may act synergistically in vivo to enhance the formation of E2 in breast tumours.
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PMID:The interaction of cytokines in regulating oestradiol 17 beta-hydroxysteroid dehydrogenase activity in MCF-7 cells. 800 40

Estradiol 17 beta-hydroxysteroid dehydrogenase (17 beta HSD) mediates the interconversion of estrone and estradiol in endocrine-responsive tissues such as the breast. The control of 17 beta HSD expression by all-trans-retinoic acid (RA) in T47D breast cancer cells was examined using a specific 17 beta HSD complementary DNA probe. Two main 17 beta HSD messenger RNA (mRNA) transcripts of 2.2 and 1.3 kilobases (kb) were detected, of which only the 1.3-kb mRNA was regulated. RA increased expression of the 17 beta HSD 1.3-kb mRNA in a dose- and time-dependent manner, and the increased expression of this mRNA by RA was inhibited by a 10-fold excess of a RA antagonist Ro 41-5253. Insulin-like-growth factor-I, interleukin-1, and estradiol, previously shown to increase 17 beta HSD activity in breast cancer cells, had little effect on 17 beta HSD gene expression. To relate the effect of increased 17 beta HSD 1.3-kb mRNA expression to 17 beta HSD activity, the conversion of estrone to estradiol (reductive) and that of estradiol to estrone (oxidative) were measured in intact T47D cell monolayers. Whereas RA increased 17 beta HSD reductive activity, it had no effect on oxidative activity. The addition of excess NAD increased 17 beta HSD oxidative activity in control and RA-treated cells, but the addition of NADH had no effect on 17 beta HSD reductive activity. These results suggest that the increased expression of the 17 beta HSD 1.3-kb mRNA induced by RA is associated with an increase in 17 beta HSD reductive activity, but that endogenous cofactor levels may determine the direction in which this enzyme acts in T47D cells.
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PMID:Regulation of estradiol 17 beta-hydroxysteroid dehydrogenase expression and activity by retinoic acid in T47D breast cancer cells. 801 76

Estradiol (E2) is well known as stimulator of the growth of 7,12-dimethylbenz(a)anthracene (DMBA)-induced mammary tumors. The effect of estrone (E1), however, has not been described in this model of human breast cancer. As E1 is the predominant estrogen precursor in postmenopausal women, we have investigated the effect of this steroid and, simultaneously, the potential role of the enzyme required for interconversion of the weak estrogen E1 into the potent estrogen E2, namely 17 beta-hydroxysteroid dehydrogenase, in the growth of DMBA-induced mammary carcinoma in the rat. Treatment for 20 days of ovariectomized animals bearing DMBA-induced mammary tumors with twice daily doses of 0.375, 0.75, 1.5, and 3.0 micrograms E1 increased total tumor area by 48%, 101%, 116%, and 129%, respectively. Treatment with the highest dose of E1 increased progesterone receptor levels by 20.4- and 2.3-fold in the DMBA-induced tumors and uterus, respectively. After treatment with E1, the concentration of this steroid was similar in the serum and tumor tissue, whereas concentrations of E2 were approximately 3-fold higher in the tumor tissue compared to serum. Treatment with a 1.0-microgram dose of E1 caused a 60% increase in tumoral 17 beta-hydroxysteroid dehydrogenase activity in ovariectomized animals, thus favoring E2 formation from E1 in tumors. In addition, treatment with the 1.0-microgram dose of E1 or 0.1 microgram E2 gave similar stimulatory effects on tumor growth and uterine weight in ovariectomized animals; the values were comparable to those found in intact animals. The present data indicate that ovariectomized rats bearing DMBA-induced mammary tumors and treated with E1 can be a useful model of postmenopausal breast cancer.
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PMID:Effect of estrone on the growth of 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma in the rat: a model of postmenopausal breast cancer. 811 75

The estrogen-sensitive human breast cancer cell line ZR-75-1 was used to study the regulation of 17 beta-hydroxysteroid dehydrogenase (17 beta HSD), the enzyme responsible for the interconversion of estrone (E1) and estradiol (E2). We, thus, investigated the effects of a 6-day exposure to various steroids or growth factors on the reductive (E1-->E2) and oxidative (E2-->E1) 17 beta HSD activities in ZR-75-1 cells as measured during a subsequent 16-h incubation with [3H]E1 or [3H]E2. The reductive 17 beta HSD activity was approximately 3-fold higher than the corresponding oxidative (E2-->E1) activity in control cells, thus favoring the predominance of E2 within the cell. Exposure to dihydrotestosterone (DHT) increased by 1.4-fold the reductive 17 beta HSD activity, with the stimulatory effect exerted at an EC50 value of 0.09 nM DHT, while the oxidative pathway was increased by 4.15-fold at an EC50 value of 0.17 nM. Incubation with medroxyprogesterone acetate, on the other hand, enhanced reductive 17 beta HSD activity by 1.87-fold, while the same treatment increased oxidative 17 beta HSD activity by 2.85-fold; the effects were exerted at EC50 values of 0.4 and 5 nM, respectively. The stimulatory effect of both steroids on 17 beta HSD activity was almost completely reversed by simultaneous exposure to the pure antiandrogen hydroxyflutamide (3 microM), thus supporting an action exerted through the androgen receptor. On the other hand, the synthetic estrogen ethynyl estradiol (EE2) inhibited the reductive and oxidative 17 beta HSD activities by 40% and 33%, respectively, whereas dexamethasone (300 nM) increased by 2.5- and 1.9-fold the reductive and oxidative 17 beta HSD activities, respectively. The present data showing that DHT and the androgenic compound medroxyprogesterone acetate favor the degradation of E2 into E1 suggest that the potent antiproliferative activity of these two compounds in E2-stimulated ZR-75-1 human breast cancer cells could be at least partially exerted through changes in 17 beta HSD activity.
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PMID:Androgen receptor-mediated stimulation of 17 beta-hydroxysteroid dehydrogenase activity by dihydrotestosterone and medroxyprogesterone acetate in ZR-75-1 human breast cancer cells. 838 Mar 73

Polyclonal antibodies produced against human placental 17 beta-hydroxysteroid dehydrogenase (17HSD), purified to homogeneity, and the corresponding cDNA for the enzyme were used to study the expression of 17HSD in a number of human tissues using various immunological methods together with RNA hybridization techniques. In addition, two 17HSD genes and their putative regulatory elements were sequenced. Immunoblotting analysis showed that the placental-type enzyme is expressed in granulosa-luteal cells, breast cancer tissue and breast cancer cell lines. An immunologically identical antigen was also detected in normal and carcinomatous human endometrium. The same antiserum, following affinity purification, was used for immunohistochemical studies of the endometrium and breast tissue, whereupon staining of the cytoplasm of the epithelial cells alone was observed. Immunostaining was also present in cultured human granulosa cells and in about half of the endometrial and breast carcinoma specimens investigated. Progesterone induction of the 17HSD enzyme protein was demonstrated in the human endometrium during the secretory phase of the menstrual cycle and in one breast cancer cell line (T-47D) following progestin treatment. There are at least two mRNAs for placental 17HSD (1.3 kb, 2.3 kb). RNA hybridization analysis of various breast cancer cell lines showed that the 1.3 kb mRNA was most closely associated with enzyme protein expression and was also the only form responding to progesterone induction. We conclude that placental-type 17HSD is also expressed in some other human tissues, both steroid-synthesizing and steroid-responding, and that the mRNA and enzyme protein are induced by progesterone. The availability of the sequence of 17HSD genes and surrounding regions allows us to study the sequences responsible for the expression and regulation of 17HSD.
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PMID:Steroid biosynthetic enzymes: 17 beta-hydroxysteroid dehydrogenase. 838 71

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