The specific binding of androgens and the subsequent distribution of androgen-receptor complexes within MCF-7 human breast cancer cells

MacIndoe, John H.; Woods, Gayle; Lee, Ferrol J.

doi:10.1016/0039-128x(81)90078-7

Cited by 9 publications

(4 citation statements)

References 11 publications

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“…First, the potency of DHT and testosterone to induce antiproliferative effects (IC 50 , ϳ0.10 and 0.50 nm, respectively) is in agreement with their relative binding affinity for androgen specific binding sites in intact ZR-75-1 cells as well as in other human breast cancer cells (219,220). Such values compare well with the potency of DHT to specifically stimulate the secretion of the Zn-␣ 2 -glycoprotein (221) and the GCDFP-15 glycoprotein (221,222) in T47-D human breast cancer cells.…”

Section: B Preclinical Datamentioning

confidence: 64%

Endocrine and Intracrine Sources of Androgens in Women: Inhibition of Breast Cancer and Other Roles of Androgens and Their Precursor Dehydroepiandrosterone

et al. 2003

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Serum androgens as well as their precursors and metabolites decrease from the age of 30-40 yr in women, thus suggesting that a more physiological hormone replacement therapy at menopause should contain an androgenic compound. It is important to consider, however, that most of the androgens in women, especially after menopause, are synthesized in peripheral intracrine tissues from the inactive precursors dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S) of adrenal origin. Much progress in this new area of endocrine physiology called intracrinology has followed the cloning and characterization of most of the enzymes responsible for the transformation of DHEA and DHEA-S into androgens and estrogens in peripheral target tissues, where the locally produced sex steroids are exerting their action in the same cells in which their synthesis takes place without significant diffusion into the circulation, thus seriously limiting the interpretation of serum levels of active sex steroids. The sex steroids made in peripheral tissues are then inactivated locally into more water-soluble compounds that diffuse into the general circulation where they can be measured. In a series of animal models, androgens and DHEA have been found to inhibit breast cancer development and growth and to stimulate bone formation. In clinical studies, DHEA has been found to increase bone mineral density and to stimulate vaginal maturation without affecting the endometrium, while improving well-being and libido with no significant side effects. The advantage of DHEA over other androgenic compounds is that DHEA, at physiological doses, is converted into androgens and/or estrogens only in the specific intracrine target tissues that possess the appropriate physiological enzymatic machinery, thus limiting the action of the sex steroids to those tissues possessing the tissue-specific profile of expression of the genes responsible for their formation, while leaving the other tissues unaffected and thus minimizing the potential side effects observed with androgens or estrogens administered systemically.

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Section: B Preclinical Datamentioning

confidence: 64%

Endocrine and Intracrine Sources of Androgens in Women: Inhibition of Breast Cancer and Other Roles of Androgens and Their Precursor Dehydroepiandrosterone

et al. 2003

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“…Several lines of evidence show that the potent growth-inhibitory effect of androgens observed in ZR-75-1 cells is mediated through their specific interaction with the androgen receptor. Firstly, the potency of 5~x-DHT and T to induce antiproliferative effects (ICs0-0.10 and 0.15 nM, respectively) is in agreement with their relative binding affinity for androgen specific binding sites in intact ZR-75-1 cells as well as in other human breast cancer cells [12,46]. It also compares well with the potency of 5(x-DHT to specifically stimulate the secretion of the Zn-~x2-glycoprotein [19] and the GCDFP-15 glycoprotein [19,20] in T47-D human breast cancer cells.…”

Section: Discussionmentioning

confidence: 94%

Androgens inhibit basal and estrogen-induced cell proliferation in the ZR-75-1 human breast cancer cell line

Poulin

Baker

Labrie

1988

Breast Cancer Res Tr

159

103

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This study describes the inhibitory effect of 5 alpha-dihydrotestosterone (5 alpha-DHT) and its precursors testosterone (T) and androst-4-ene-3,17-dione (delta 4-DIONE) on the growth of the estrogen-sensitive human breast cancer cell line ZR-75-1. In the absence of estrogens, cell proliferation measured after a 12-day incubation period was 50-60% inhibited by maximal concentrations of 5 alpha-DHT, T, or delta 4-DIONE with half-maximal effects (IC50 values) observed at 0.10, 0.15 and 15 nM, respectively. This growth inhibition by androgens was due to an increase in generation time and a lowering of the saturation density of cell cultures. The antiestrogen LY156758 (300 nM) induced 25-30% inhibition of basal cell growth, its effect being additive to that of 5 alpha-DHT. The mitogenic effect of 1 nM estradiol (E2) was completely inhibited by increasing concentrations of 5 alpha-DHT with a potency (IC50 = 0.10 nM) similar to that measured when the androgen was used alone. E2 had a more rapid effect on cell proliferation than 5 alpha-DHT, the latter requiring at least 5 to 6 days to exert significant growth inhibition. As found in the absence of estrogens, maximal inhibition of cell proliferation in the presence of E2 was achieved by the combination of the antiestrogen and 5 alpha-DHT. Supraphysiological concentrations of E2 (up to 1 microM) were needed to completely reverse the growth inhibitory effect of a submaximal concentration of 5 alpha-DHT (1 nM). The antiproliferative effect of androgens was competitively reversed by the antiandrogen hydroxyflutamide, thus indicating an androgen receptor-mediated mechanism. The present data suggest the potential benefits of an androgen-antiestrogen combination therapy in the endocrine management of breast cancer.

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“…Finally, a number of studies have revealed cell surface receptors for these steroid binding proteins (1,(14)(15)(16)(17)(18). In the present study we have demonstrated the binding of TeBG by MCF-7 cells, which are known to be responsive to both androgens (22) and estrogens (43). These data include specific binding sites for TeBG on the cell surface, temperature-dependent latency, and movement through classic sub-cellular organelles involved in endocytosis.…”

Section: Discussionmentioning

confidence: 48%

“…The fact that several serum proteins, including corticosteroidbinding globulin (CBG) (17,18), transferrin (19), and low density lipoprotein (20), bind to specific membrane receptors and are internalized by receptor-mediated endocytosis (21) suggested that TeBG might enter cells by the same mechanism. To investigate this possibility we studied this process using MCF-7 cells in which intracellular immunoreactive TeBG has been found (2) and which androgen has been shown to influence (22).…”

mentioning

confidence: 99%

Receptor-Mediated Endocytosis of an Extracellular Steroid-Binding Protein (TeBG) in MCF-7 Human Breast Cancer Cells*

et al. 1991

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Previous studies suggested that an extracellular steroid-binding protein, testosterone-estradiol-binding globulin (TeBG), can enter a variety of cells. Experiments were conducted to determine whether uptake of TeBG occurs by nonspecific fluid phase endocytosis or via a specific receptor-mediated process. In human breast carcinoma cells (MCF-7) maintained on serum-free medium, exposure to radiolabeled TeBG resulted in cellular uptake, which reached a plateau by 6 h and could be inhibited 80% by competition with unlabeled TeBG. Uptake was temperature dependent with cell-associated radioactivity at 37 C being 1.6-fold higher than at 4 C. Subsequent exposure of cells to pronase resulted in release of the cell-associated TeBG by 88% and 44% at 4 C and 37 C, respectively. After transfer to media devoid of TeBG, approximately 35% of cell-associated radioactivity was release into the medium at 37 C; it was not possible to distinguish whether this was released from the cell surface or from inside the cell. Investigation of the localization of TeBG-gold complexes by electron microscopy revealed that TeBG first binds to the plasmalemma. Within 15 min label appears in receptosomes, which fuse to form multivesicular endosomes. By 1 h all label is observed in multivesicular endosomes and lysosomes, most of which are in the Golgi zone. Localization of the internalized radioactivity using classical cell fractionation techniques showed it appears in a symmetrical band exhibiting the same buoyant density as the lysosomal marker acid phosphatase. The observations reported here show that: 1) TeBG binds to MCF-7 cells; 2) some of the bound TeBG is taken up via a mechanism with all the characteristics of receptor-mediated endocytosis; and 3) within these cells TeBG is localized in endosomes and lysosomes.

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The specific binding of androgens and the subsequent distribution of androgen-receptor complexes within MCF-7 human breast cancer cells

Cited by 9 publications

References 11 publications

Endocrine and Intracrine Sources of Androgens in Women: Inhibition of Breast Cancer and Other Roles of Androgens and Their Precursor Dehydroepiandrosterone

Endocrine and Intracrine Sources of Androgens in Women: Inhibition of Breast Cancer and Other Roles of Androgens and Their Precursor Dehydroepiandrosterone

Androgens inhibit basal and estrogen-induced cell proliferation in the ZR-75-1 human breast cancer cell line

Receptor-Mediated Endocytosis of an Extracellular Steroid-Binding Protein (TeBG) in MCF-7 Human Breast Cancer Cells*

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