Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present study we have explored the actions of the progestagen R5020 (Promegestone: 17 alpha, 21-dimethyl-19-nor-pregna-4, 9-diene-3,20-dione) and progesterone on the uptake of [3H]estrone sulfate ([3H]E1S) and its conversion to estradiol (E2) by two hormone-dependent mammary cancer cell lines: MCF-7 and T-47D. R5020 or progesterone significantly decreased the uptake of [3H]E1 and its conversion to (E2). In the cells of the two lines, R5020 or progesterone (5 x 10(-6) M) decreased the E2 concentrations by 2-3 times in relation to the levels in untreated cells. E1S (1 x 10(-7) M) also increased expression of the progesterone receptor (PR) and both R5020 (5 x 10(-6) M) and progesterone (5 x 10(-6) M) blocked this stimulatory action of E1S in cells of both cell lines. As E2 is one of the main factors of cancerization in the breast and estrone sulfate is quantitatively the most important precursor of E2 in this tissue, the decrease of E2 by these progestagens could open new possibilities for the control of E2 in the breast cancer tissue.
 ...
PMID:Effect of the progestagen R5020 (promegestone) and of progesterone on the uptake and on the transformation of estrone sulfate in the MCF-7 and T-47d human mammary cancer cells: correlation with progesterone receptor levels. 145 Oct 96

In order to determine growth effects of the progestin R5020, (promegestone), we have utilized the progesterone-receptor rich human breast cancer cell line T-47D, growing the cells in the absence of the pH indicator phenol red, which has recently been found to be estrogenic. In contrast to reports on cells grown in the presence of phenol red, we find that promegestone alone, at physiological progestin concentration, significantly stimulates growth. Estradiol alone, at physiological concentration, stimulates growth much more. Promegestone in combination with estradiol is antiestrogenic for growth; that is, it significantly decreases the growth stimulatory effect of estradiol. These results raise the possibility that estrogen receptor and progesterone receptor-rich breast cancer patients might benefit more from a combination of anti-progestin and anti-estrogen therapy than from anti-estrogens alone.
 ...
PMID:Progestin effects on growth in the human breast cancer cell line T-47D--possible therapeutic implications. 359 65

The biological activities of promegestone (R 5020), used world-wide as a radioligand for the progestin receptor, are described. Promegestone is a potent progestin devoid of androgenic side-effects and has marked anti-estrogenic activity. Its therapeutical effectiveness (0.125 mg or 0.250 mg) in luteal insufficiency has been established in a double-blind clinical trial versus dydrogesterone (10 or 20 mg) which revealed its significantly superior potency (p less than 0.001). On the basis of the pharmacological data described, its use in cancer therapy according to a sequential protocol for the treatment of hormone-dependent breast cancer and in psychiatry to palliate the psychological disorders of the premenstrual syndrome and the perimenopause seems promising.
 ...
PMID:[Promegestone, a new progestin]. 636 37

The evaluation of estrogens (estrone, estradiol, and their sulfates) in the breast tissue of post-menopausal patients with breast cancer indicates high levels, particularly of estrone sulfate (E1S) which is 15-25 times higher than in the plasma. Breast cancer tissue contains the enzymes necessary for local synthesis of estradiol and it was demonstrated that, despite the presence of the sulfatase and its messenger in hormone-dependent and hormone-independent breast cancer cells, this enzyme operates particularly in hormone-dependent cells. Different progestins: Nomegestrol acetate, Promegestone, progesterone, as well as Danazol, can block the conversion of E1S to E2 very strongly in hormone-dependent breast cancer cells. The last step in the formation of estradiol is the conversion of E1 to this estrogen by the action of 17 beta-hydroxysteroid dehydrogenase. This activity is preferentially in the reductive direction (formation of E2) in hormone-dependent cells, but oxidative (E2-->E1) in hormone-independent cells. Using intact hormone-dependent cells it was observed that Nomegestrol acetate can block the conversion of E1 to E2. It is concluded, firstly, that in addition to ER mutants other factors are involved in the transformation of hormone-dependent breast cancer to hormone-independent, this concerns the enzymatic activity in the formation of E2; it is suggested that stimulatory or repressive factor(s) involved in the enzyme activity are implicated as the cancer evolves to hormone-independence; secondly, different drugs can block the conversion of E1S to E2. Clinical trials of these "anti-enzyme" substances in breast cancer patients could be the next step to investigate new therapeutic possibilities for this disease.
 ...
PMID:Estrone sulfate-sulfatase and 17 beta-hydroxysteroid dehydrogenase activities: a hypothesis for their role in the evolution of human breast cancer from hormone-dependence to hormone-independence. 762 88

The effects of the synthetic progestin R5020 and the antiprogestin RU486 on the cellular content of estrogen receptors (ER) and on cell responsiveness to estrogens, have been investigated in the sex hormone-sensitive human breast cancer cell lines MCF-7 and T47D. When T47D cells were treated with R5020 (Promegestone) (10(-8) M), ER was down-regulated to about 50% of the control level in a time-dependent manner. Maximum down-regulation was observed after 24 hours and remained at this level for the next 24 hours. Dihydrotestosterone (DHT) or dexamethasone (DEX) had no effect on ER sites. R5020 also down-regulated, although to a lesser extent, ER in the MCF-7 cells which contain fewer progesterone receptor (PR) sites. When MCF-7 cells were transfected with a progesterone receptor expression vector (tMCF-7) to increase the number of PR sites, R5020 down-regulated the ER to a level similar to that reached in T47D cells. In both cell lines ER down-regulation was completely inhibited by a 10-fold molar excess of the antiprogestin RU486 (Mifepristone) (10(-7) M). Surprisingly, when incubated with RU486 alone, T47D cells responded by up-regulating ER 2-4 fold. The functional relevance of inhibition and up-regulation of ER for the estrogen responsiveness of hormone-sensitive human breast cancer cells was tested by assaying the synthesis of an estrogen-regulated product, the PS2 protein. Estrogen induction of this protein was inhibited by at least 70% in T47D cells exposed to R5020 for 24 hours before estrogen administration and by about 25% in MCF-7 cells under the same conditions.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Progesterone agonists and antagonists induce down- and up-regulation of estrogen receptors and estrogen inducible genes in human breast cancer cell lines. 762 27

Using different hormone-dependent (MCF-7, T-47D) and hormone-independent (MDA-MB-231, Hs-578S, MDA-MB-436) human breast cancer cells, the interconversion estrone (E1)<-->estradiol (E2) was explored. The data show very clearly that in the hormone-dependent cells the tendency is to form E2 after incubation with E1, whereas after incubation with E2 most of this estrogen remains unchanged. In the hormone-independent cells, in contrast most of E1 remains E1, while E2 is converted into E1. The tendency of the reductive<-->oxidative direction is supported by the analysis of estrogens in the culture medium. To explore the possible action of different drugs on the 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) activity, it was observed that the potent antiestrogen ICI 164,384 inhibits the conversion of E1 to E2, while a lesser effect is observed with Danazol and only weak inhibition is obtained with the progestagen Promegestone (R-5020). It is concluded that the orientation of 17 beta-HSD activity for the interconversion E1<-->E2 in hormone-dependent and -independent cells is related to the hormonal status of the cells.
Breast Cancer Res Treat 1995 May
PMID:Transformation of estrone and estradiol in hormone-dependent and hormone-independent human breast cancer cells. Effects of the antiestrogen ICI 164,384, danazol, and promegestone (R-5020). 764 31

Using reverse transcriptase polymerase chain reaction amplification it was possible to detect the presence of oestrogen sulphatase mRNA in different hormone-dependent (MCF-7, T-47D) and hormone-independent (MDA-MB-231, MDA-MB-468) mammary cancer cell lines. The expression of this mRNA is significantly higher in T-47D and MDA-MB-231 than in the other cell lines, and a correlation of this expression with the enzymatic activities was observed. The progestagen Promegestone (R-5020) can significantly decrease the mRNA of the sulphatase in MCF-7 cells. As this progestagen can also inhibit the enzyme itself in the same mammary cancer cell line, it is suggested that for the decrease in the sulphatase activity not only the effect on the enzyme, but also the effect on transcriptional factor(s) which express this enzyme are involved. The present data not only contribute to the knowledge of the mechanism of the sulphatase activity, but also can open new possibilities in breast cancer treatment.
 ...
PMID:Effect of the progestagen Promegestone (R-5020) on mRNA of the oestrone sulphatase in the MCF-7 human mammary cancer cells. 797 90

In the present study, we explored the effects on sulphatase activity by Promegestone (R-5020), Tamoxifen (TAM), 4-hydroxytamoxifen (4-OH-TAM) and ICI 164,384 in the T-47D hormone-dependent and MDA-MB-231 hormone-independent mammary cancer cell lines. Using homogenates of these cells it was observed that Promegestone has a significant effect on the inhibition of oestrone (E1) sulphatase activity. As this effect is competitive, it is suggested that there is a direct action of this compound on the enzyme. Tamoxifen has very little or no effect, 4-hydroxytamoxifen has an intermediate effect and ICI 164,384 is active in the enzyme inhibition, particularly with MDA-MB-231 cells. The present data could open new possibilities for human breast cancer treatment, as sulphatase is very active in the first step of the conversion of oestrone sulphate (E1S) to oestradiol (E2), and oestradiol is one of the principal carcinogenic factors in human hormone-dependent breast cancer.
 ...
PMID:Effect of promegestone, tamoxifen, 4-hydroxytamoxifen and ICI 164,384 on the oestrone sulphatase activity of human breast cancer cells. 835 61

In our previous work we reported on stimulation of a tissue unspecific alkaline phosphatase (liver/bone/kidney, L/B/K) in the human breast cancer cell line T47D by progestins. Here we show that in these cells the synthetic progestin R5020 (Promegestone) induces transcription of a 2.7-kilobase ALP mRNA. In this cel line, maximal induction is reached after 24 hours, decreases to 50% after 72 hours and is sensitive to inhibitors of protein synthesis. The induction of ALP mRNA and enzyme activity is specific for R5020 and dexamethasone and is completely inhibited in the presence of 10(-7) M RU486. When treated with R5020 for 48 hours, T47D cells exhibit a substantially altered phenotype, lipid vacuoles accumulate all over the cytoplasm, conferring to the cells a secretory morphology. This phenotype is associated with increased ALP enzyme activity which is also maximal at 48 hours. This effect is progestin specific since other steroids do not lead to the same macroscopical changes.
 ...
PMID:Progesterone induced expression of alkaline phosphatase is associated with a secretory phenotype in T47D breast cancer cells. 850 82

Breast cancer tissue contains the enzymes necessary for local synthesis of estradiol (E2) and it was demonstrated that, despite the presence of the sulfatase and its messenger in hormone-dependent and hormone-independent breast cancer cells, this enzyme operates particularly in hormone-dependent cells. Different progestins: Nomegestrol acetate, Promegestone, Tibolone (Org OD14) and its metabolites (Org-OM38, Org 4098 and Org 30126), as well as Danazol, can block the conversion of estrone sulfate to E2 very strongly in hormone-dependent breast cancer cells. The last step in the formation of E2 is the conversion of estrone (E1) to estrogen by the action of 17 beta-hydroxysteroid dehydrogenase. This activity is preferentially in the reductive direction (formation of E2) in hormone-dependent cells, but oxidative (E2-->E1) in hormone-independent cells. Using intact hormone-dependent cells, it was observed that Nomegestrol acetate. Promegestone as well as Danazol, can block the conversion of E1 to E2. Clinical trials of these "anti-enzyme" substances in breast cancer patients could be the next step to investigate new therapeutic possibilities for this disease.
 ...
PMID:Role, control and expression of estrone sulfatase and 17 beta-hydroxysteroid dehydrogenase activities in human breast cancer. 936 95


1