Target Tissues For Steroid Hormones Research Articles

Synchronous primary malignancies in breast and kidney: a rare case report.

Multiple synchronous malignancies are rarer than metachronous ones. Primary synchronous breast and renal cancer is even rare. Such a case requires strict exclusion of possible metastasis to either site and to confirm the primary nature of each malignancy for better outcome of management and survival benefit. Multiple primary synchronous malignancies may be due to shared genetic mutations if any common carcinogenic factor cannot be found. The role of estrogens in cases in which human renal carcinoma is associated with other primary tumours involving steroid-hormone target tissues, is tentative and can only be hypothesised due to paucity of such data in literature. One should consider the possibility of concomitant dual or multiple primary tumours in a patient presented with mass lesions at various sites, especially if one of the sites is the kidney. We present a case report of a patient with synchronous primary breast and renal cancer.

The glucocorticoid receptor is specifically expressed in the stromal compartment of the human endometrium.

The human endometrium is a classical target tissue for steroid hormones. While the expression pattern and functional roles of both the estrogen receptor (ER) and the progesterone receptor (PR) are well defined, expression of the glucocorticoid receptor (GR) in this tissue has not been described so far. In the present study, we used immunohistochemistry to analyze the expression of GR in the normal human endometrium throughout the menstrual cycle. The expression of GR was compared to that of ER and PR, which were analyzed in parallel. We show that GR is expressed in the human endometrium with a pattern that markedly differs from the expression patterns of ER and PR. ER and PR are expressed in the nuclei of endometrial glands, whereas GR is completely absent from these structures. However, GR is strongly expressed in the stromal compartment of the endometrium throughout the cycle. Both stromal fibroblasts and lymphocytes are GR-positive. In addition GR expression is also observed in the endothelium of small endometrial blood vessels, which are ER- and PR-negative. Western blot analysis performed on endometrial tumor cell lines of glandular (HEC-1B) and mesodermal (SKUT-1B) origin, respectively, showed GR expression only in the latter. In summary, we demonstrate that GR is expressed in fibroblasts, lymphocytes and endothelial cells of the human endometrial stroma, while it is absent from the glandular compartment. The specific expression pattern of GR within the human endometrium points to a possible functional role of glucocorticoids in the process of decidualization which occurs primarily in the stromal compartment.

Multiple primary tumors: 17 cases of renal-cell carcinoma associated with primary tumors involving different steroid-hormone target tissues.

The aim of this study was to analyze the characteristics of 17 women with renal-cell carcinoma (RCC) associated with other primary neoplasms occurring in steroid-hormone target tissues. The reproductive history of these patients and the use of exogenous hormones were taken into consideration. In all, 10 RCCs were associated with breast carcinoma; 4, with endometrial carcinoma; and 3, with ovarian carcinoma. The presentation of a second primary tumor was described as synchronous or metachronous by evaluation of the interval between the discovery of the two neoplasms. Hormone and surgical treatment as well as pathologic findings for each primary tumor were also reported. In these 17 RCCs the overall rate of disease-specific survival recorded after a mean follow-up period of 32.7 months (range 9-66 months) was 58.8%; 7 patients died of metastatic disease after surviving for a mean of 14.7 months. In terms of the pathologic stage of RCC, a significant difference in mean survival was found between pN0 (mean survival 22.1 +/- 3.4 months) and pN1 RCCs (mean survival 13.7 +/- 3.5 months). A total of 13 (76.4%) women were postmenopausal at the time of diagnosis of the first primary tumor; the mean age of these women at menopause was 51.7 +/- 1.2 years. No prior use of oral contraceptives was reported by 12 (70.5%) of the 17 patients. Plasma 17-beta-estradiol and estrone levels were determined in only 7 patients at the diagnosis of each of the primary tumors. High plasma estrogen levels were found in 4 women with RCC and breast carcinoma and in 1 patient with RCC and endometrial carcinoma; in the remaining 2 patients low-normal values were found. A relationship appears to exist between certain reproductive and hormone-related factors and the risk of developing these tumor associations. Data emerging from the present study do not provide strong support for the hypothesis of hormone dependency of RCC; however, a role for estrogens in cases in which RCC is associated with other primary tumors involving steroid-hormone target tissues can be hypothesized.

Ultrastructural distribution of steroid sulfatase activity and mRNA in the human kidney

Steroid sulfatase (STS) is a microsomal enzyme catalyzing hydrolysis of 3β-hydroxysteroid sulfatases, including dehydroepiandrosterone sulfate, cholesterol and estrogen precursors. STS exists widely in various tissues and is involved in the metabolism of steroid hormones which play a critical role in cell proliferation and may be related to cancer induction in several organ systems. In the kidney, the proximal and distal portions of the nephrons have been suggested as possible sites of synthesis or as target tissues for steroid hormones. However, the presence and the role of STS in the human kidney have not been fully investigated. In this study, we examined the distribution of STS activity and mRNA in human renal tissue by enzyme histochemistry and in situ hybridization at the light and electron microscopic level.Renal tissue specimens were taken from normal areas in the surgically resected kidney from patients with renal cancer. STS activity was analyzed by enzyme histochemistry using 4-methylumbelliferyl sulfate. STS-mRNA distribution was detected by in situ hybridization using an STS cDNA probe cloned from human placenta.

Hormone-sensitive lipase is involved in the hydrolysis of lipoidal derivatives of estrogens and other steroid hormones

Long-chain fatty acid esters of 17β-estradiol and other steroid hormones, which are formed in hormone-sensitive tissues, can be regenerated to the free hormone by the action of an esterase present in the cytosol. This esterase has now been examined in bovine placenta cotyledons. Activity towards steroid fatty acid esters was accompanied by activity towards a diacylglycerol analogue and cholesteryl oleate. During purification procedures, the ratio of activities towards the diacylglycerol analogue and estradiol 17β-oleate remained approximately constant. Activity towards these two substrates was inhibited by increasing concentrations of HgCl 2 and phenylmethanesulfonyl fluoride in a parallel manner. Upon treatment with [ 3H]diisopropyl fluorophosphate, a major labelled species of M r approx. 84000 was formed. Activation by ATP and the catalytic subunit of cAMP-dependent protein kinase occurred. These properties were very similar to those of the hormone-sensitive lipase of bovine adipose tissue previously reported and run in parallel in this study. A highly purified preparation of this latter enzyme was found to hydrolyse steroid fatty acid esters and relative activities towards such substrates, diacylglycerol analogue and cholesteryl oleate, were similar to the placenta esterase. When the two esterases were phosphorylated with [γ- 32P]ATP, a labelled species of M r 84000 was isolated in both cases by use of an antibody raised against purified hormone-sensitive lipase of bovine adipose tissue. It is concluded that hormone-sensitive lipase is very likely the enzyme responsible for hydrolysis of steroid fatty acid esters in bovine placenta and possibly steroid hormone target tissues in general.

Microsomal receptor for steroid hormones: Functional implications for nuclear activity

Target tissues for steroid hormones are responsive by virtue of and to the extent of their content of functional intracellular receptors. Recent years have seen a shift in considerations of the cellular dynamics and distribution of these receptors, with current views favoring predominant intranuclear localization in the intact cell. This paper summarizes our analyses of the microsomal estrogen and androgen binding capability of rat uterine and ventral prostate tissue, respectively; these studies have revealed a set of high affinity sites that may act as a conduit for estrogen traversing the cell en route to the nucleus. These sites have many properties in common with cytosolic receptors, with the salient difference of a failure to activate to a more avid DNA-binding form under conditions which permit such activation of cytosolic receptors. The microsomal estrogen-binding proteins also have appreciable affinity for progesterone, another distinction from other known cellular estrogen receptor species. Various experimental approaches were employed to demonstrate that the microsomal receptors were not simply cytosol contaminants; the most convincing evidence is the recent successful separation of the cytosolic and microsomal forms by differential ammonium sulfate precipitation. Discrete subfractionation of subcellular components on successive sucrose gradients, with simultaneous assessments of binding capability and marker enzyme concentrations, indicates that the major portion of the binding is localized within the vesicles of the endoplasmic reticulum free of significant plasma membrane contamination.The microsomal receptors are readily solubilized by extraction with high- or low-salt-containing buffers or with steroid. The residual microsomes following such extraction have the characteristics of saturable acceptor sites for cytosolic estrogen-receptor complexes. The extent to which these sites will accept the cytosolic complexes is equal to the concentration of microsomal binding sites extracted. These observations suggest three possible roles for the microsomal receptor-like proteins: (a) modulation of estrogen access to nuclear binding sites; (b) formation of functional complexes which diffuse to other extranuclear sites to alter non-genomic cellular processes; (c) regulation of nuclear concentration of estrogen-receptor complexes by virtue of producing microsomal acceptor sites for uptake of free or loosely associated nuclear complexes, previously thought to exist in the cytoplasm.

Estrogen and progestin receptors in acoustic and spinal neurilemmomas.: Clinicopathologic correlations

Estradiol and progestin receptors were studied in 20 patients with neuraxial Schwann cell tumors, and their presence was correlated to the clinicopathologic features and the amount of preoperative corticosteroid therapy. Based on an arbitrary cutoff value of 200 fmol per gram of tumor as indicative of a positive receptor value in breast cancer, 4 and 13 of the neurilemmoma tissue samples could be considered as positive for estrogen and progesterone receptors, respectively. Whereas there was no convincing correlation between the estrogen and progestin receptor activity and the age, sex, or menopausal status of the patients, overweight patients had significantly higher estrogen and progestin binding values. The correlation between the amount of preoperative prednisone therapy and the amount of [ 3H]estradiol and [ 3H]promegestone binding revealed no dose relationship. Correlating [ 3H]estradiol and [ 3H]promegestone content with the histologic type of the schwannomas (Antoni types A and B, respectively), we were not able to draw conclusions, because of the predominance of Antoni type A over Antoni type B tissues in our material. The necessity of nuclear receptor assays, ligand specificity testing, and in vitro studies is stressed as a prerequisite for answering the questions whether neurilemmomas contain genuine sexual steroid hormone receptors and whether these receptors are regulated via an estrogen-estrogen-receptor system as is the case in classical sexual steroid hormone target tissues.

Determination of steroid hormone-dependency of tumours utilizing tissue sections. Survey of histochemical techniques and their application in surgical pathology.

The growth of neoplasms originating from steroid hormone target tissues may be hormone-dependent. It has been clearly demonstrated that the oestrogen and/or progestagen receptor status predicts the response to endocrine treatment and the prognosis of breast cancer. However steroid receptor determination in tumour cytosols has several limitations, which can partly be resolved by (immuno) histochemical detection of steroid hormone-responsive tumour cells. A variety of histochemical techniques including autoradiography of tritiated steroids, immunohistochemistry with antibodies to steroid hormones, histochemistry with fluorescent ligands of low molecular weight and fluorochrome- or enzyme-labelled macromolecular probes are discussed. It is concluded that there is as yet no substantial evidence that these methods visualize steroid receptors or detect steroid hormone-responsiveness of tumour cells. On the other hand, immunohistochemical demonstration of oestrogen receptors with monospecific antibodies seems validated and indications have been obtained that this information is clinically relevant. Recent developments suggest that immunocytochemistry of receptors and specific hormone-induced proteins, flow cytometric analysis and probably hybridocytochemistry in the future will help to improve management of steroid hormone-dependent tumours.

Antagonism of glucocorticoid action in cultured hepatoma cells

We report here our recent data on the effects of antiglucocorticoids in two established cell lines (HTC, FAZA). These steroid hormone target tissues were designed to consider the problem of differential antagonism and lack of correlation between antiglucocorticoid activity and competition for the glucocorticoid receptor. In the systems chosen, several responses were considered which may be differentially antagonized: induction of tyrosine aminotransferase (TAT), alanine aminotransferase (AAT) and tryptophan oxygenase (TPO). By testing the anti-inducing capacities of a number of steroids, we found a few synthetic compounds like promegestone and R 25055 which exert a stronger antagonism against TAT and AAT induction than natural steroids like progesterone. The availability of highly radioactive antagonists (promegestone, progesterone) has greatly facilitated our “whole cell” study and allowed us to detect the antagonists in isolated nuclei whose purity and morphological integrity were controlled by specific criteria; our results suggest that the binding of the antagonists to the nucleus proceeds via the glucocorticoid receptor. The appearance of promegestone and progesterone in the nucleus suggests that the nucleus may be involved in the mechanism of action of anti-glucocorticoids.

Adenyl cyclase and the cyclic AMP responsive systems in the uterus.

Thus far in this symposium, we have been treated to a detailed, thoughtful and elegant presentation of the current status of the steroid hormone responsive systems in various tissues. The role of the adenyl cyclase system in steroid hormone target tissues has received far less attention (1–3) so we initiated studies both to define its role in uterine function and ultimately to determine whether there is an interaction with the steroid responsive system. The uterus seemed like an ideal subject tissue for such studies because it serves as the target for a variety of hormones, including oligopeptides, biogenic amines and steroids.

Soluble complexes between steroid hormones and target-tissue receptors bind specifically to target-tissue chromatin.

Cytoplasmic fractions containing steroid hormone receptor were prepared from rat prostate and uterine tissues, incubated first with [(3)H]dihydrotestosterone or [(3)H]estradiol, and then with their respective target and non-target tissue chromatins. Only prostate and testis chromatin bound the dihydrotestosterone-receptor complex from prostate cytosol extensively. Similarly, uterine chromatin bound more estradiol-receptor complex from uterus than did liver, spleen, or lung chromatin. Complexes between dihydrotestosterone or estradiol with cytosols prepared from liver and spleen bound less extensively, and similarly, to all chromatins. Analogous results are described for the [(3)H]progesterone-receptor complex from chick oviduct cytosol binding to oviduct chromatin. These studies suggest that the chromatin of all steroid hormone target tissues may contain "acceptor sites" for their respective hormone-receptor complexes, and are thus programmed to receive the complex as it is transferred into the nucleus from the cytoplasm of the cell.