Danazol and non-Hodgkin's malignant lymphomas.
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Androgens↗
Biomedical subjects
S Saez
Publications and source records attributed to S Saez.
1,25-Dihydroxyvitamin D3 inhibitory effect on the growth of two human breast cancer cell lines (MCF-7, BT-20).
1,25 (OH)2 D3 has been shown to be able to reduce the growth of several human cell lines. The effect of 1,25 (OH)2 D3 on the growth of breast cancer cell lines in relation to their oestrogen (ER) and progesterone (PGR) receptor content has been investigated. The growth inhibition of BT-20 and MCF-7 cell lines is related to the dose of 1,25 (OH)2 D3. It is dependent on the foetal calf serum concentration in the culture medium. At low concentration of 1,25 (OH)2 D3 the inhibitory effect is not detectable in the presence of 10% FCS. The rescue of cells from inhibition by serum was less effective when 1,25 (OH)2 D3 was present in the medium. The results of [3H]thymidine incorporation experiments and DNA measurements are in agreement with the reduction of cell number. Analysis in flow cytometry indicated a reduced number of cells in S phase. These data indicate that 1,25 (OH)2 D3 is able to modulate the growth of human breast adenocarcinoma cells regardless of their sex steroid dependency.
Breast Neoplasms↗
Androgens increase osteoblast-stimulating activity of human breast cancer cells in vitro.
Bone metastases of breast cancers produce not only osteolytic but also osteosclerotic lesions. The latter are often observed after androgenic treatment of the tumor. Potential production of osteoblast stimulating activity (ObSA) in breast cancer cell lines, and possible androgen control of this activity have been investigated. Conditioned media (CM) collected from 4 breast cancer cell lines (MCF-7, ZR75, MDA-MB 231, BT20) was tested in vitro on ROS 17/2,8 osteoblast-like cells and on osteoblasts derived from human bone biopsies. The parameters monitored in osteoblasts were [3H]thymidine incorporation, alkaline phosphatase activity, and osteocalcin secretion. Serum-free media conditioned during 24 h by MCF-7 cells presented the highest ObSA. CM decreased thymidine incorporation in DNA and increased alkaline phosphatase activity in a dose-dependent manner. Bone GLA protein (osteocalcin) secretion by human osteoblasts was not increased however in the presence of CM. MCF-7 cells were cultured in the presence of dihydrotestosterone (DHT) [1-100 nM] for 5 days. Serum-free, DHT-free CM collected after an additional 24 h, contained alkaline-phosphatase stimulating activity which was DHT dose-dependent. Estradiol and 1,25(OH)2D3 failed to elicit a comparable increase of the ObSA in the CM. In conclusion, MCF-7 cells product factor(s) that interfere with bone remodeling. The DHT modulation of ObSA parallels the estradiol control of MCF-7 cells osteolytic lesions in relation with Prostaglandin E secretion. Sex hormones at physiological and pharmacological levels might thus control both osteosclerotic and osteolytic lesions observed in bone deposits of hormone dependent cancers.
Androgens↗
Distribution of androgen and estrogen receptors among lymphoid and haemopoietic cell lines.
Estrogen receptors (ER) and androgen receptors (AR) were determined in a series of 23 leukemia or lymphoma cell lines including 8 T-cell lines, 12 B-cell lines, and 3 non lymphoid cell lines. The phenotypic characterization of these cells by currently available immunological markers provides an estimate of their stage of differentiation. The result indicate that none of the investigated cell lines bear simultaneously ER and AR. Four were found to bear ER: U266, RPMI 8226, HL60, IARC/310/LT2, and four to express AR: RAJI, IARC/301/LTI, U937, REH6. The presence of cytosolic receptors was always associated with that of nuclear receptors. The expression of either ER or AR is restricted to discrete maturation stages of different haemopoietic cell lineages. Thus AR were found among the most immature lines of the T, B or monocytic lineage but they could be detected neither in the promyelocytic line HL60, nor in the pluripotential K562. The present results are in keeping with the demonstration of AR in some leukaemic blasts or in non Hodgkin's lymphomas. In contrast with AR, ER are present in two myeloma cell lines, in the promyelocytic cell line, HL60 and in a T-cell line bearing the phenotype of mature suppressor/cytotoxic T cells.
Cell Line↗
Estrogens and antiestrogens stimulate release of bone resorbing activity by cultured human breast cancer cells.
Patients with advanced breast cancer may develop acute, severe hypercalcemia when treated with estrogens or antiestrogens. In this study, we examined the effects of estrogens and related compounds on the release of bone resorbing activity by cultured human breast cancer cells in vitro. We found that the estrogen receptor positive breast cancer cell line MCF-7 releases bone resorbing activity in response to low concentrations of 17 beta-estradiol. Bone resorbing activity was also released in response to the antiestrogen nafoxidine. Other steroidal compounds had no effect on the release of bone resorbing activity. Estrogen-stimulated release of bone resorbing activity occurred with live bone cultures, but not with devitalized bones, indicating that the effect was bone cell mediated. The breast cancer cell line MDA-231, which does not have estrogen receptors, did not release bone resorbing activity in response to 17 beta-estradiol or nafoxidine. Release of the bone resorbing activity by MCF-7 cells incubated with 17 beta-estradiol was inhibited by indomethacin (10 microM) and flufenamic acid (50 microM), two structurally unrelated compounds that inhibit prostaglandin synthesis. Concentrations of 17 beta-estradiol and nafoxidine that caused increased release of bone resorbing activity by the breast cancer cells caused a four- to fivefold increase in release of prostaglandins of the E series by MCF-7 cells. These data may explain why some patients with advanced breast cancer develop acute hypercalcemia when treated with estrogens or antiestrogens, and why bone metastases are more common in patients with estrogen receptor positive tumors.
Biological Products↗
[Resorption and formation in metastatic bone].
Bony metastases are a source of numerous complications and remain a difficult therapeutic target. Malignant cells implant in bony tissue where they can secrete factors which stimulate resorption and/or bone formation. The nature of these factors is now being discovered, even though their mode of action is better understood: the osteolytic action of prostaglandin E2 secreted in breast cancer, or the osteogenesis stimulating action of "transforming growth factor" in prostatic cancer. Progress in these areas of research is soon forthcoming due to new techniques in molecular biology.
Bone Neoplasms↗
[Antiestrogens].
Antioestrogens are synthetic non-steroidal compounds which compete for oestrogen receptors. They induce a biological effect in various oestrogen target tissues in peripheral and central organs, but other mechanisms of action that do not involve oestrogen receptors are possible. Depending on the species and organ investigated, the biological effect may vary from pure antioestrogenic to pseudo-oestrogenic. Antioestrogens reduce the growth of oestrogen-dependent tumours in target organs or tissues which contain oestrogen receptors and are therefore successfully used in the treatment of hormone-dependent tumours, e.g. adenocarcinoma of the breast. They are generally well tolerated, but should be used with caution, owing to their endocrine side-effects. Combinations with other hormones to enhance their therapeutic effectiveness are currently being investigated.
Animals↗
Influence of endogenous hormone levels on tumor estradiol and progesterone receptors.
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Adult↗
Estrogen and progesterone receptors as prognostic factors in early breast cancer.
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Breast Neoplasms↗
High affinity cytosol binding site(s) for antiestrogens in two human breast cancer cell lines and in biopsy specimens devoid of estrogen receptors.
It is known from previous investigations by other authors that the non-steroidal molecule Tamoxifen competes for estradiol binding sites in target tissues and displays partial agonist-antagonist effects. It is able to bind a cytosol protein distinct from ER which has been detected in target tissues, as well as in fetal target and non-target organs. The present work investigates the antiestrogen binding activity of human breast cancer cell lines and tumor biopsies. It is found that BT-20 and MDA-MB 231 cell lines devoid of ER and PGR contain a cytosol protein component able to bind antiestrogens with a high affinity (= 2 X 10(-9) M). The 3H-labeled complex prepared in hypotonic buffer sediments at 6.25 S in a sucrose gradient. A substantial amount of antiestrogen binding sites is found to be linked to the microsomal cell fraction, in agreement with previous data from other investigators. In experiments using whole cells incubated at 37 C, the complex is depleted from the cytosol compartment. A low amount of radioactivity is extracted from the purified nuclei. In the cytosol of human breast tumor biopsies the presence of antiestrogen binding sites is not exclusively associated with the presence of ER and PGR. The identity of the natural ligand which binds to these sites under physiological conditions merits investigation.
Binding, Competitive↗
How culture conditions modulate the morphofunctional differentiation of the human estradiol-sensitive mammary cell line (MCF-7).
The MCF-7 cell line grown on plastic surfaces is widely accepted as a model for hormone sensitivity in molecular biology. However, in vitro results concerning estrogen sensitivity remain controversial. In search of culture conditions most closely simulating the in vivo microenvironment we cultured MCF-7 cells on diverse substrates and in suspension culture. The different factors of the contact environment: (A) influence of diffusive medium, (B) influence of cell to cell contacts, and (C) influence of cell to substrate contacts were considered. Using morphological criteria:phase contrast microscopy, scanning and transmission electron microscopy we observed MCF-7 morphofunctional differentiation under the different culture conditions. Plastic, corneal endothelial cell extracellular matrix, and attached collagen gels imposed a planar medium-aggregate interface. The impermeability of the free surface and the intense basal tension antagonized epithelial polarization. Only at post-confluence did domes and clusters appear above the monolayer. On floating collagen gels and in suspension culture the cells established intimate cell-cell contacts over large surfaces and reconstituted tissular architecture. Three-dimensional growth conditions which approach the in vivo contact environment of epithelial cells should be used instead of the traditional monolayer cultures for assessing hormonal and pharmacological responses of human breast carcinomas.
Breast Neoplasms↗
Characterization of a specific androgen receptor in non-Hodgkin's lymphoma cells.
The use of a competitive binding assay has permitted us to detect a cytoplasmic androgen receptor in cells of node biopsies of several patients suffering from non-Hodgkin's malignant lymphomas (NHML). These same cells appear to contain very low or undetectable numbers of estrogen receptor. The androgen receptors are saturated at approximately 2 X 10(-10) M [3H] 5 alpha DHT and Scatchard analyses of the binding data indicated a high affinity constant (Kd = 0.29 +/- 0.19 10(-9) M). The range of receptor sites is 19-327 fmol/mg protein (median = 42 fmol/mg protein). These cytoplasmic receptors are inactivated at 37 degrees C and pronase. The [3H] 5 alpha DHT receptor complex migrates in linear 5-20% sucrose gradients with a sedimentation coefficient of 7S and this peak is shifted to the 4S region under high salt conditions. Physiochemical properties of the binding including binding capacity and steroid specificity, are quite similar to those reported in target organs.
Adolescent↗
Prognostic value of estrogen and progesterone receptors in primary breast cancer.
Estradiol receptor alone or estradiol and progesterone receptors (ER, PgR) have been measured in tumors from 307 women who were treated for primary breast adenocarcinoma. Patients received adjuvant therapy in relation to tumor stage independently of receptor status. Over a relatively short follow-up, more recurrences are recorded in patients with ER+ tumors, but at 7 years the same proportion of recurrences are registered in both groups of patients whose tumors were ER+ or ER-. Patients whose tumors were processed for both ER and PgR (148 cases) have now been evaluated after 5 years follow-up. Among 56 patients with PgR+ tumors 5 recurred, versus 22/92 in the PgR- group. 21/87 patients who had 1 to 4 invaded nodes at the time of surgery relapsed: 17/54 had PgR- tumors versus 4/33 PgR+. 6 recurrences were recorded in the 61 patients with negative nodes: 5 of them occurred in patients with PgR- tumors. In addition, recurrences observed in patients with negative receptor status occurred after a shorter disease-free interval. Analysis of the incidence of recurrences in relation to the combined ER/PgR status in patients who did not receive adjuvant therapy suggests that tumor PgR content is a more significant criterion than ER for long-term prognosis.
Adenocarcinoma↗
Specific estrogen binding sites in human lymphoid cells and thymic cells.
The binding of estrogen in preparations of human peripheral blood mononuclear cells, as well as by splenic and thymic cells is demonstrated by three different approaches (Dextran-coated charcoal method, whole cell assay, and gel filtration on a sepharose 4B column). Scatchard's analysis of [3H]-moxestrol (R2858) and [3H]-estradiol binding proves the existence of a single class of receptor sites having a dissociation constant of 0.18-2.4 X 10(-9) M. Physicochemical properties of the binder, including binding capacity and steroid specificity, are quite similar to those reported for the thymus of small mammalian species or human thymoma.
Humans↗
[Hormone receptors and breast cancer prognosis].
Estradiol and progesterone assays in breast cancer have been developed for ten years and their clinical significance investigated in primary and metastatic tumors. The presence of estradiol and/or progesterone receptor is not related to the extension of the disease, the age of the patient or hormonal status. It seems to be related to the grade of histological differentiation. 1) Clear relationship exists between the presence of estradiol receptor and hormone dependency. 2) Estrogen receptor positive tumors demonstrate a more favorable outcome than the estrogen receptor negative one. According to recent data the presence of progesterone receptor is a better criteria than ER for long term pronostic.
Breast Neoplasms↗
Sex steroid receptors in peripheral T cells: absence of androgen receptors and restriction of estrogen receptors to OKT8-positive cells.
The immune response has been reported to be modulated by sex hormones in several models, and estrogen receptors have been demonstrated in the human thymus. We therefore investigated the presence of estrogen and androgen receptors among human peripheral T cells; thoracic duct lymph provided large amounts of circulating lymphocytes. Pure T cells were obtained by negative selection by using complement-dependent cytotoxicity with a monoclonal antibody against a monomorphic determinant of class II histocompatibility antigen (HLA-DR). Furthermore, subsets of OKT8-positive and OKT8-negative lymphocytes were selected by using an OKT8-like monoclonal antibody. Sex steroid binding was determined on purified nuclei; no androgen receptors could be demonstrated on peripheral T cells. The cytoplasmic [3H] 17-beta-estradiol-receptor complex was always translocated to the nucleus in vitro within 1 hr at 37 degrees C; no estrogen receptors were demonstrable on purified OKT4-positive subsets. Assuming that estrogen receptors were evenly distributed among OKT8-positive cells, their level could be estimated to be about 40 fmol/mg DNA. The restriction of estrogen receptors to T cells bearing the "suppressor-cytotoxic" phenotype suggests a possible pathway for the modulation of T cell suppressive activities by estrogens.
Adult↗
Tamoxifen-induced fluorescence as a marker of human breast tumor cell responsiveness to hormonal manipulations: correlation with progesterone receptor content and ultrastructural alterations.
The fluorescent binding of tamoxifen to eosin is used on Papanicolaou-stained smears as a marker of cell responsiveness to the antiestrogen molecule. Forty-two cases of human breast carcinomas were submitted to tamoxifen treatment between first diagnosis and surgery (4 to 30 days). Tamoxifen-induced fluorescence is observed in 17 of 42 cases (40%). There is a highly significant correlation between progesterone receptor content of the tumor and cellular fluorescence (0.01 greater than p greater than 0.001). Ultrastructural changes of such tumors (820 cells observed in 28 treated patients and 840 cells in 32 untreated controls) are observed in 42% of treated cells versus 10% of untreated cells. These ultrastructural alterations can be significantly correlated with cellular fluorescence induced by tamoxifen treatment and with progesterone receptor content of human breast cancers. These data suggest that a short pretreatment with tamoxifen before surgery can give useful additional information at the biochemical, cytochemical, and ultrastructural levels regarding cell responsiveness to hormonal manipulation.
Breast Neoplasms↗
Presence of estrogen binding sites and growth-stimulating effect of estradiol in the human myelogenous cell line HL60.
In the present study, we investigated the effects of estrogens on the growth of the HL60 line in vitro and the presence of estrogen binding sites in the same cells. Cell proliferation was estimated by cell counts, [3H]thymidine incorporation, and determination of the percentage of cells in the S phase by flow cytometry. Cells maintained in a medium containing physiological concentrations of estradiol (10(-9) M, 10(-8) M, 10(-7) M) exhibited a growth stimulation, shown by an increase in the percentage of cells in the S phase, whereas a pharmacological concentration (10(-6) M) produced a growth inhibition. Furthermore, the addition of the specific antihormone, tamoxifen, inhibited the stimulating effect of the estrogens. Receptor analysis showed the presence of specific estrogen-binding sites with an apparent dissociation constant of about 5.3 X 10(-10) M. The effect of estrogen was therefore associated with the presence of estrogen receptors in the human leukemic cell line HL60.
Cell Division↗