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Biomedical subjects

J B Adams

Publications and source records attributed to J B Adams.

At least 19 recordsLinked to original sources
PubMed1992

Human breast cancer: concerted role of diet, prolactin and adrenal C19-delta 5-steroids in tumorigenesis.

The low incidence of breast cancer in Japan disappears within 2 generations in migrant Japanese in the USA. This is of fundamental importance if we are to understand, and perhaps reverse, the high rate seen in Western countries. Diet is the most likely factor involved, and a review of the topic of diet, body mass index, and gain in adult body mass, supports a relationship between these factors and breast-cancer risk in post-menopausal, but not pre-menopausal, women. A direct link between nutritional factors and secretion of the hormones prolactin and dehydroepiandrosterone sulfate is proposed. An estrogen 5-androstene-3 beta, 17 beta-diol is formed peripherally from the latter steroid, and in Western women attains a blood concentration at which it is biologically active. Thus diet/fat provides factors, viz., fatty acids, prolactin and estrogen, which in concerted fashion provide a milieu conducive to mammary tumorigenesis.

Adrenal Glands↗
PubMed1992

Regulation of estrogen sulfotransferase by estrogen in MCF-7 human mammary cancer cells.

The importance of the steroid hormone microenvironment within cells is now recognised in studies on endocrine-related neoplasms such as breast cancer. This focuses attention on enzymes which control the intracellular levels of estradiol-17 beta (E2). One such enzyme, estrogen sulfotransferase, which converts E2 to inactive E2-3 sulfate, has now been shown to be regulated by estrogen in MCF-7 human mammary cancer cells. Hydroxysteroid sulfotransferase, which sulfurylates the adrenal-derived estrogen 5-androstene-3 beta,17 beta-diol, is also under estrogen control. Evidence is provided which shows that one function of these enzymes may involve elimination of estrogen from the cell following processing of the ligand-charged estrogen receptor (ER).

Breast Neoplasms↗
PubMed1992

Enzymatic regulation of estradiol-17 beta concentrations in human breast cancer cells.

Estradiol-17 beta is known to be involved in both the etiology and maintenance of growth of breast cancer. However, blood levels of the hormone do not reflect those found within the cells due to a number of transformations catalysed by enzymes which may be under metabolite and/or hormonal regulation. Recognition of the importance of the hormone microenvironment within the cell focuses attention on these enzymes and provides the subject for this review. An interplay between the sex hormones, estrogen and progestin, can control estradiol-17 beta concentrations in breast cancer cells at the level of key transforming enzymes. In addition, some enzymes catalyse production of biologically inert derivatives which are rapidly eliminated from the cell. Other enzymes catalyse the formation of derivatives which are exclusively intracellular and can act as reserve forms of the hormone. Yet others lead to estradiol-17 beta metabolites which are cytotoxic. An improved understanding of the enzymes and the role of the related metabolites can provide the opportunity for the development of new therapeutic agents.

Breast Neoplasms↗
PubMed1992

Estrogen receptor and C19-5-ene-steroid concentrations in the nuclear fraction from human breast carcinoma tissue.

The adrenal-derived estrogen 5-androstene-3 beta,17 beta-diol (ADIOL) is estrogenic at the concentrations found in the blood of Western women. We have now measured the concentrations of both ADIOL and the estrogen receptor (ER) in the nuclear fraction (800 g pellet) of 89 primary human mammary tumors. No difference was found in nuclear ADIOL concentrations in tumors from 45 pre- and 44 postmenopausal women. Significantly higher nuclear ADIOL concentrations were found in 49 ER negative tumors compared to 40 ER positive tumors (P < 0.005). A similar relationship applied in the postmenopausal group (P = 0.01) and the premenopausal group, but in this latter instance failed to reach significance (P = 0.1). In ER positive tumors there was no correlation between ADIOL and ER nuclear levels. ADIOL was present in the total particulate fraction (100,000 g pellet) at twice the concentration found in the nuclear 800 g pellet and again no difference was found in its concentration in tumors from 20 pre- compared to 34 postmenopausal women. Dehydroepiandrosterone was also measured in the 800 g fraction of 45 tumors and its concentration, which was some 10-fold higher than ADIOL and significantly correlated with that steroid, was again independent of menopausal status. The higher concentration of C19-5-ene-steroids in ER negative cellular fractions could be due to differences in their metabolism; ER negative tumors either lack, or possess very low levels of, hydroxysteroid sulfotransferase which catalyzes formation of sulfate esters of C19-5-ene-steroids previously observed to be major metabolites produced by ER positive cells. Higher concentrations of free steroids in ER negative cells would then be available for combination with membranes and non-specific binding sites throughout the cell.

Androstenediol↗
PubMed1991

Enzymic synthesis of steroid sulphates. XVII. On the structure of bovine estrogen sulphotransferase.

Estrogen sulphotransferase plays a major role in controlling intracellular levels of 17 beta-estradiol in human mammary cancer cells and human endometrium. Bovine estrogen sulphotransferase c-DNA has recently been cloned; the encoded protein having a maximum Mr of 35,000 (Nash, A.R. et al. (1988) Aust. J. Biol. Sci. 41, 507-516). Enzyme of Mr 35,000 by SDS-PAGE has now been isolated and cyanogen bromide-cleaved peptides sequenced. The latter were identified in the c-DNA-predicted amino acid sequence which confirms that the active enzyme (Mr approximately 70,000) exists as a dimer of identical subunits. Sequence data on similar peptides isolated from an enzyme preparation containing a protein of Mr 74,000 as the major species on SDS-PAGE, which was previously thought to represent the enzyme, suggested that this protein was transferrin. This was confirmed by PAGE, SDS-PAGE, susceptibility to neuraminidase and reaction with bovine transferrin antibody. Isoelectric focusing experiments show that active enzyme exists in two or three polymorphic forms (pI values 5.3, 5.7 and possibly 5.9) having similar physicochemical properties of polymorphic forms of transferrin so that they overlap on ion-exchange chromatography and PAGE. The enzyme shows some homology to the amino acid sequence close to the Fe-binding site in lactoferrin and the question is raised as to the possible presence of a tightly bound metal in estrogen sulphotransferase involved in the binding of adenosine 3'-phosphate 5'-phosphosulphate.

Amino Acid Sequence↗
PubMed1991

Metabolism of lipoidal derivatives of estradiol-17-beta in human mammary cancer tissue and cell lines.

Estradiol-17 beta (E2) is converted exclusively to intracellular metabolites, termed lipoidal estrogens [long chain fatty acid 17 beta-esters (E2-L)], by human mammary cancer tissue and cell lines. In order to further evaluate the biological role of lipoidal estrogens, rates of saturation of the estrogen receptor (ER) along with formation of [3H]E2-L have been measured in human mammary cancer cells exposed to 5 nM [3H]E2. Extensive specific binding of E2 to ER in MCF-7 cells (approximately 37%) and ZR-75-1 cells (approximately 62%) occurred before appreciable synthesis of E2-L was evident and the maximum level of E2-L attained was only 3-9% of the E2 specifically bound to ER. In these ER positive cell lines, and in the ER negative cell line MDA-MB-231, an initial rise in the rate of E2-L formation was followed by a decrease at approximately 6 min and re-establishment of a new rate, indicating turnover of the E2-L fraction by esterification-de-esterification reactions. This data does not support the concept that E2-L acts in the transport of E2 to nuclear receptors, but rather than liberation of E2 from E2-L could serve to maintain occupancy of ER necessary for initiation of DNA synthesis. The esterase, as studied in pooled human mammary cancer tissue, was found to hydrolyse E2-17 beta-long chain fatty acid esters at different rates--the enzyme being less active towards E2-17 beta-stearate compared to E2-17 beta-oleate, -linoleate and -linolenate. Esterase activity was significantly higher in MDA-MB-231 cells compared to MCF-7 cells. Treatment of MCF-7 cells with E2 did not alter the specific activity of the esterase towards E2-17 beta-oleate as substrate. Similarly, addition of dibutyryl c-AMP to ZR-75-1 cell cultures was without effect on E2-L, both during the time when E2-L was accumulating, or during a subsequent phase when E2-L was decreasing following transfer to medium lacking E2. Calcitonin, which increases endogenous c-AMP in MCF-7 cells, had no effect on E2-L in this latter phase using this cell line. Thus, no evidence could be provided that the esterase was under E2 control, or control by polypeptide hormones which utilize c-AMP as a second messenger.

Breast Neoplasms↗
PubMed1990

Properties of estrogen and hydroxysteroid sulphotransferases in human mammary cancer.

Partial purification (approximately x 140-fold) of estrogen sulphotransferase (EC 2.8.2.4) in human mammary estrogen receptor positive cancer tissue was achieved by affinity chromatography on adenosine-3',5'-diphosphate-agarose. It had a Mr of approximately 70,000 by gel filtration and upon electrophoresis on concave gradient polyacrylamide gels, showed a major (Mr 70,000) and a minor (Mr 200,000) peak of activity. Kinetics of this preparation (estradiol-17 beta and estrone as substrates), and also that of hydroxysteroid sulphotransferase (EC 2.8.2.2) contained in the cytosol of human mammary cancer MCF-7 cells (5-androstene-3 beta,17 beta-diol and dehydroepiandrosterone as substrates), were compared. The enzymes showed very similar behaviour, characterized by high affinity for their steroid substrates (low nM range) and co-operativity in their binding. For hydroxysteroid sulphotransferase, the adrenal-derived estrogen 5-androstene-3 beta,17 beta-diol was the preferred substrate compared to dehydro-epiandrosterone in the 0-40 nM concentration range. Such properties of the enzymes might be designed to limit the exposure of nuclear receptor to free ligand. Alternatively, a defined subcellular location would perhaps involve the enzymes in the elimination of estrogen after processing of the ligand-bound receptor.

Breast Neoplasms↗
PubMed1989

Expression of hydroxysteroid sulphotransferase is related to estrogen receptor status in human mammary cancer.

A positive correlation between the expression of estrogen sulphotransferase (EC 2.8: 2.4) and the estrogen receptor (ER) in human breast cancer tissues was previously demonstrated. We have now established that a similar correlation exists between the expression of hydroxysteroid sulphotransferase (EC 2.8: 2.2) and ER in such tissues. Enzyme activity was present in 93% of the ER + tumor cytosols (mean 59 +/- 44 (SD) pmol dehydroepiandrosterone sulphate formed per mg protein per 2 h (n = 42). Activity was detected in 68% of ER - tumors and this was significantly lower (mean 21 +/- 26 (SD) (n = 19), P less than 0.001) than the former group. Metabolism of estradiol-17 beta (E2) and the adrenal-derived estrogen 5-androstene-3 beta, 17 beta-diol (ADIOL), which is a substrate for hydroxysteroid sulphotransferase but not estrogen sulphotransferase, was studied in four ER + human mammary cancer cell lines (MCF-7, T47-D, MDA-MB-361 and ZR-75-1) and four ER-human mammary cell lines (BT-20, MDA-MB-231, MDA-MB-330 and HBL-100), employing steroid concentrations of 1 nM. At this concentration, formation of ester sulphates was a major route of metabolism in the ER + cell lines; E2 yielding a mean of 6.5 pmol estrogen monosulphates/mg DNA in 16 h and ADIOL yielding a mean of 9.4 pmol C19-5-ene steroid monosulphates/mg DNA in 16 h. In three of the four ER - cell lines, formation of sulphates from E2 occurred at an eight-fold lower rate (mean 0.8 pmol estrogen sulphates/mg DNA in 16 h), whereas MDA-MB-330 cells did not form estrogen sulphates. Only one of the four ER- cell lines (BT-20) sulphurylated ADIOL and this was at a 12-fold lower rate compared to the mean value for the ER + cel lines. Oxidation of E2 and ADIOL occurred in all cell lines and was generally the major route of metabolism in the ER - cells. A significant correlation between formation of estrone and dehydroepiandrosterone occurred for all cell lines (r = 0.98, P less than 0.001) indicating that the same 17 beta-hydroxysteroid dehydrogenase was probably involved. Since ADIOL is estrogenic in a number of systems at the concentration found in the blood of Western women (approximately 2 nM), the coordinated expression of hydroxysteroid sulphotransferase, estrogen sulphotransferase, and ER, supports the concept of a functional relationship between estrogen action via ER and sulphurylation reactions.

17-Hydroxysteroid Dehydrogenases↗
PubMed1989

Formation of glucuronides of estradiol-17 beta by human mammary cancer cells.

The formation of glucuronides of estradiol-17 beta by human mammary cancer cell lines is reported for the first time. When incubated with [3H]estradiol-17 beta (1 nM) for 16 h, ZR-75-1 and T47-D cells formed estradiol-3-glucuronide and estradiol-17 beta-glucuronide in approximately equal proportions, whereas MCF-7 cells formed E2-3-glucuronide only. Yields of monoglucuronides from MCF-7 and ZR-75-1 cells were 0.35 pmol/mg DNA, which represented 20-26% of the yield of estradiol-monosulphates. A HPLC system capable of separating most estradiol monosulphates, monoglucuronides and mixed conjugates, is described.

Breast Neoplasms↗
PubMed1989

Long-chain fatty acid esters of 5-androstene-3 beta, 17 beta-diol: composition and turnover in human mammary cancer cells in culture.

Long-chain fatty acid esters of the adrenal-derived estrogen 5-androstene-3 beta, 17 beta-diol (ADIOL) were found to accumulate in four human mammary cancer cell lines (MCF-7, ZR-75-1, MDA-MB-231 and MDA-MB-330) when explosed to 10-30 nM ADIOL for variable time periods. At each time point examined, the monoester fraction, which represented the major component of the total lipoidal fraction, contained fatty acids linked to either the 3 beta- or 17 beta-positions. However, there was considerable variation in the ratio of 3 beta- to 17 beta-monoesters in the four cell lines. By means of reverse phase HPLC and referral to authentic synthesized compounds, each monoester fraction was found to contain a number of long-chain fatty acid components whose composition resembled that previously determined for the fatty acid esters formed from 17 beta-estradiol. A specific and measurable turnover of a subfraction of ADIOL-17 beta-monoesters composed of essential fatty acids (22:6, 20:4, 18:3) occurred in MCF-7 cells, and to a lesser extent in ZR-75-1 cells. No changes were observed with time in any of the components of the 3 beta- or 17 beta-monoester fractions in MDA-MB-231 and MDA-MB-330 cells. These results, coupled with other studies, now suggest that a very rapid turnover of some components of these lipoidal derivatives may be occurring. If so, it is possible that the system of acylation-deacylation may be involved in a transport mechanism for estrogens and perhaps other steroid hormones.

Acylation↗
PubMed1979

A correlation between estrogen sulfotransferase levels and estrogen receptor status in human primary breast carcinoma.

Estrogen sulfotransferase (EC 2.8.2.4) activity and estrogen receptor levels were measured in 32 human primary breast cancer cytosol preparations. Two types of tumors were identified: type 1, in which estrogen sulfotransferase levels were low (less than 40 pmol 17 beta-estradiol 3-sulfate formed per mg protein per 2 hr) and were independent of [35S]adenosine 3'-phosphate 5'-phosphosulfate production from [35S]sulfate and adenosine triphosphate, and type 2, in which estrogen sulfotransferase levels ranged from 50 to 200 pmol 17 beta-estradiol 3-sulfate per mg protein per 2 hr and were correlated with [35S]adenosine 3'-phosphate 5'-phosphosulfate formation (r = 0.70; p less than 0.005). In type 1 tumors, 11 of 16 were estrogen receptor negative; in type 2 tumors, 2 of 16 were receptor negative. Estrogen sulfotransferase levels in receptor-negative tumors were significantly lower than the levels in receptor-positive tumors (p = 0.025).

Breast Neoplasms↗
PubMed1978

Discontinuous transition of myelin structure at the junction between central and peripheral components of the eighth cranial nerve, as disclosed by X-ray diffraction.

Scanning along human acoustovestibular nerves from cross-sections closely proximal to the brain to locations distinctly peripheral thereto, by means of small-angle X-ray diffraction, has disclosed transitional junctions at which the myelin structure typical of central nervous system (CNS) axons gives way to one characteristic of peripheral (PNS) fibers. The junctions correspond to regions along the nerves, previously recognized histologically, at which the satellite cells responsible for axon myelination change character, from the oligodendrocytes of the CNS to the Schwann cells of the PNS. Thus the structural discontinuity between the CNS and PNS myelins can be ascribed to differences in the biosynthetic processes of the respective satellite cells. Junctions of this kind are to be expected in all cranial and spinal roots near the locations where they leave the CNS.

Humans↗
PubMed1978

Products of dehydroepiandrosterone metabolism by human mammary tumors and their influence on estradiol receptor binding.

The high concentrations of dehydroepiandrosterone and its 3beta-sulfate in the blood are potential preocursors for further metabolism by normal and tumorous human mammary tissue. In vitro metabolism of 7n-3H- and 1,2,6,7(n)-3H-dehydroepiandrosterone by fifteen mammary tumors was examined. Some 10--50% of the radioactivity recovered was in the form of 7-oxygenated derivatives: the major metabolite being 7alpha-hydroxydehydroepiandrosterone accompanied by lesser amounts of the 7beta-epimer. 5-Androstene-3beta,17beta-diol was formed in all but one case. Evidence showed that the high yield of 7alpha-hydroxy derivative resulted from direct action of a 7alpha-hydroxylase capable of using both dehydroepiandrosterone and 5-androstene-3beta,17beta-diol as substrates. Although 5-androstene-3beta,17beta-diol competed with estradiol-17beta for the estrogen receptor, this property was considerably reduced as a consequence of the introduction of a 7alpha-hydroxyl or 16alpha-hydroxyl group. Dehydroepiandrosterone, which competed less effectively for the estrogen receptor site, showed almost no affinity for the site upon the introduction of a 7alhpa-hydrocyl group. A regulatory role for the 7alpha-hydroxylase is outlined.

Androstenediols↗