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Dexamethasone, Fortecortin, Breast Cancer, Iodine uptake, Apoptosis, BLV, MMTV (Answer 4)
Stand / Letzte Aktualisierung durch Elisabeth Rieping 23.07.2007
Answers to Question 4: What is wrong? Dexamethasone (Fortecortin)
a) Induces mammary gland development
Dexamethasone has a lactogenic effect which is known in the diary industry.
Using a combination of dexamethasone, estrogen and progesteron it is possible to induce milk production in heifers (young cows) before pregnancy, as these hormones induce the development of the breast epithelium without pregnancy. (Delouis 1978,Chakriyarat, Head et al. 1978; Head, Chakriyarat et al. 1982; Fowler, Knight et al. 1991; Ball, Polson et al. 2000). b) Cooperates with insulin in differentiation of breast epithelial cells Dexamethasone, insulin and prolactin together can induce the differentiation of breast epithelial cells and the production of casein mice and probably in other animals, too. (Marte, Meyer et al. 1994, Marte, Jeschke et al. 1995) In the presence of dexamethasone there seems to be no involution after weaning (Feng, Marti et al. 1995). c) Induces mammary tumor viruses Dexamethasone is the strongest inducer of the mouse mammary tumor virus MMTV which had wondered many researchers, because its lactogenic effect is not very known.
In 1997 Niermann and Buehring showed that Dexamethasone also induces the bovine leukemia virus BLV. BLV is an oncogenic retrovius which causes a B-cell leukemia in cattle. Like MMTV it is transmitted by milk. In this case by bovine milk. Its DNA provirus ist is integrated in the DNA of milk lymphocytes. By cooking or other heat based methods this DNA does not get destroyed. The DNA ist is sufficient for transfection. BLV belongs to the BLV/HTLV group. HTLV-1 causes many diseases of man. The most well kown are an acute T-cell leukemia ATL and a neurodegenerative disease which is difficult to distinguish from multiple sclerosis. The HTL viruses are transmitted by breast milk, too as is the a little bit more distant relative HIV or Aids Virus. d) Promotes iodide uptake of breast cancer cells This had first been observed by Eskin, who did much of the early work on iodide uptake of breast cells, but was tested again by a Los Angelos group working on the improvement of iodide uptake of breast tumor cells for a treatment of metastases of breast cancer with radioactive iodide 131. (Kogai T, Kanamoto Y, Li AI, Che LH, Ohashi E, Taki K, Chandraratna RA, Saito T, Brent GA, 2005) This kind of treatmenat of breast cancer metastases is very interesting because the iodide uptake is specific for breast cancer and only few other cells. A major advantage to most medicines. More than 80% of breast cancers seem to take up iodide and keep it for relativly long time, as the exit, the milk, is not produced by most breast cancer cells.
e) inhibits apoptosis Dexamethasone seems to be able to inhibit apoptosis of breast cancer cells. That might be a problem, because Dexamethasone it is often used during chemotherapy of breast cancer patients to prevent nausea and vomitting. Mikosz, C. A., D. R. Brickley, et al. (2001). Wu, W., S. Chaudhuri, et al. (2004). Wu, W., T. Pew, et al. (2005).
All statements are correct
Kogai T, Kanamoto Y, Li AI, Che LH, Ohashi E, Taki K, Chandraratna RA, Saito T, Brent GA) Differential regulation of sodium/iodide symporter gene expression by nuclear receptor ligands in MCF-7 breast cancer cells.Endocrinology. 2005 Jul;146(7):3059-69. Molecular Endocrinology Laboratory, Veterans Affairs Greater Los Angeles Healthcare System, David Geffen School of Medicine at the University of California, Los Angeles, CA 90073, USA. The sodium/iodide symporter (NIS) mediates iodide uptake in lactating breast tissue and is expressed in some breast cancers. We have previously demonstrated that all-trans retinoic acid (tRA) stimulates NIS gene expression and the selective cytotoxic effect of beta-emitting radioiodide-131 ((131)I) in both in vitro and in vivo MCF-7 breast cancer cell systems. We studied the ability of natural and synthetic retinoids, in combination with other nuclear receptor ligands, to achieve greater and more sustained induction of NIS in MCF-7 cells and enhance (131)I-mediated cytotoxicity. Selective stimulation of retinoic acid receptor (RAR) beta/gamma produced marked NIS induction; and selective stimulation of RARalpha, RARgamma, or retinoid X receptor produced more modest induction. Maximal NIS induction was
seen with 9-cis retinoic acid and AGN190168, a RAR beta/gamma-agonist. Dexamethasone (Dex), but not the other nuclear receptor ligands, in combination with tRA synergistically induced iodide uptake and NIS mRNA expression, predominantly by prolonging NIS mRNA half-life. The addition of Dex reduced the EC(50) of tRA for NIS stimulation to approximately 7%, such that 10(-7) m tRA with addition of Dex enhanced iodide uptake and selective cytotoxicity of (131)I greater than 10(-6) m tRA alone. AGN190168 combined with Dex synergistically increased iodide uptake and significantly prolonged induction (5 d) of iodide uptake compared with that induced by the combination of tRA/Dex or 9-cis retinoic acid/Dex. The addition of Dex reduced the effective dose of retinoid and prolonged the induction of NIS, especially with AGN190168, suggesting higher efficacy of (131)I after combination treatment.
Laktogene Hormone – Stillhormone
Das wirksamste Hormon zur Aktivierung des Maus Mamma Tumor Virus war immer das Dexamethason, das auch unter dem Handelsnamen Fortecortin bekannt ist. Es gehört zu den Glucocorticoiden. Das verursachte allerdings Verwunderung. Denn als man die Wirkung des Dexamethasons auf die Aktivierung des Maus Mamma Tumor Virus erkannte, war es nicht bekannt, dass Glucocorticoide und zu diesen gehört Dexamethason in der Stillzeit die Milchproduktion aufrecht erhalten. Vermutlich ist das in der Humanmedizin immer noch nicht sehr bekannt, denn die meisten Informationen darüber finden sich in Zeitschriften der Milchwirtschaft. Bei der Chemotherapie von Krebserkrankungen wird es zur Unterdrückung von Übelkeit und Erbrechen eingesetzt. Und wenn man bedenkt, dass dadurch vielleicht Tumorviren gefördert werden können, ist das nicht ganz unbedenklich (Wu, Chaudhuri et al. 2004) . Bei der Rheumatischen Arthritis wird es in das Gelenk installiert, um den entzündlichen Prozess zu unterdrücken.
Anwendung des Fortecortins(Dexamethasons) in der Medizin
Auch bei entzündlichen Prozessen des Auges wird es benutzt. Zuerst wurde Cortison aber als Gegenspieler des Insulins in Bezug auf den Blutzuckerspiegel bekannt. Während Insulin die Glucose aus dem Blut in die Zellen schickt, sorgen seine Gegenspieler die Cortisone für die Erhöhung des Glucosespiegels im Blut, wie wir schon in der Schule gelernt haben. So wird unter Stress Cortison ausgeschüttet, das den Blutzucker erhöht, damit man zum Beispiel Energie zum Weglaufen oder Kämpfen hat. Wirkung auf die Milchproduktion Auf die Milchproduktion hat das Dexamethasone kurzfristig einen dämpfenden Effekt. Sie wird vorrübergehend unterdrückt. (Andersson and Olsson 1984) , weil in manchen Stress Situationen, in denen Glucocorticoide ausgeschüttet werden, ein hoher Blutzuckerspiegel wichtiger ist, als die Säuglingsernährung. Möglicherweise passiert das durch die Behinderung, der durch Saugen ausgelösten Prolaktin Ausschüttung (Bartha, Nagy et al. 1991) . Die Senkung der Milchproduktion dauert nicht lange und da Glucocorticoide oft stressbedingt ausgeschüttet werden, kann man annehmen, dass diese Wirkung die Milchproduktion vielleicht nur in kurzen Momenten der Gefahr, Flucht vor einem Raubtier oder in ähnlichen Situationen die Milchbildung unterdrücken soll. Denn abgesehen von der kurzen Unterdrückung der Milchproduktion bei Stress gehören die Cortisone zu den laktogenen Hormonen also Milch fördernden Hormonen, was in der Milchwirtschaft wichtig zu wissen ist. So kann man mit Dexamethason, Insulin und Prolaktin, den sogenannten laktogenen also Milch fördernden Hormonen, die Differenzierung und die Casein Produktion in Brustdrüsen Epithelzellen von Mäusen (Marte, Meyer et al. 1994) (Marte, Jeschke et al. 1995) und vermutlich auch in anderen Tieren
auslösen.. Auch die Lipogenese in der Brustdüse wird durch Dexamethason gefördert (Couto, Couto et al. 1998) . In der Stillphase wird die Milchproduktion durch den Saugreiz und die Anwesenheit der drei Stillhormone aufrechterhalten. In Gegenwart von Dexamethasone und Insulin kann sich die Brustdrüse nach dem Abstillen nicht zurückbilden (Feng, Marti et al. 1995) . Da die Zeit der Milchproduktion, die günstigste für die Weitergabe eines Milchvirus ist, wundert es nicht, dass diese Viren über einen Cortison aktivierbaren Promotor gerade in dieser Zeit aktiviert werden. Aber auch schon vor der Stillzeit wirkt Dexamethason auf die Brustentwicklung ein. So kann mit einer Kombination aus Östrogen, Progesteron und Dexamethason schon vor deren Pubertät die Milchproduktion in Rindern ausgelöst werden, (Delouis 1978) , (Chakriyarat, Head et al. 1978; Head, Chakriyarat et al. 1982; Fowler, Knight et al. 1991; Ball, Polson et al. 2000) , weil diese Hormone die Entwicklung des Brustdrüsengewebes bewirken, ohne das eine Schwangerschaft vorausgegangen ist. Die Entwicklung der Epithelzellen zu aktiven Brustdrüsenzellen und die spätere Milchproduktion sind zwei Prozesse, die beide nötig sind, um die Milch zu produzieren und sind beide abhängig von den laktogen Hormonen. Die Aktivierung, der mit der Milch transportierten Viren durch die gleichen Hormone (Niermann and Buehring 1997) , sorgt dafür, dass sie mit der Milch weitergegeben werden und so in den nächsten Wirt gelangen können. Das ist wahrscheinlich der natürliche Verbreitungsmodus dieser Viren wie BLV, MMTV, HTLV und HIV. Evolutionäre Vorteile des durch laktogene Hormone aktivierbaren Promotors Andere Möglichkeiten in einen neuen Wirt zu gelangen können sich durch den Geschlechtsverkehr über einen Transport mit dem Sperma ergeben, durch verseuchte Blutprodukte bei Transfusionen und
Die hormonelle Steuerung der Virusaktivierung durch Stillhormone.
ähnliche Vorgänge. Auch das Essen eines infizierten Tieres könnte zur Übertragung führen. So sollen zum Beispiel die Aids Viren von infizierten Affen, in denen sie keine Krankheit verursachen, in die Menschen gelangt sein. Der durch Stillhormone aktivierbare Promotor spricht aber dafür, dass der Weg über die Milch für das Virus vermutlich einige Vorteile bietet. Einer könnte in der Infektion zu einem frühen Zeitpunkt im Laufe des Lebens liegen, in dem der neue Wirt das Virus noch nicht als fremd erkennt und so keine Immunantwort gegen das infektiöse Agens ausgelöst wird.
Andersson, L. and T. Olsson (1984). "The effect of two glucocorticoids on plasma glucose and milk production in healthy cows and the therapeutic effect in ketosis." Nord Vet Med 36(1-2): 13-8. In a cross-over study of six clinically healthy cows in early lactation, injection of 10 mg dexamethasone isonicotinate caused significantly increased plasma glucose for six days and significantly decreased milk yield for one day. The corresponding effects of 10 mg dexamethasone phosphate + 20 mg dexamethasone phenylpropionate lasted for at least nine and seven days, respectively. The therapeutic effect in bovine ketosis of the two preparations was measured by means of analysis of acetone plus acetoacetate in milk sampled daily during eight days post treatment. Acetone plus acetoacetate in milk from cows given dexamethasone phosphate + dexamethasone phenylpropionate (n = 11) decreased to normal levels and from the fourth day after treatment was significantly lower than in cows given dexamethasone isonicotinate (n = 12).
Ball, S., K. Polson, et al. (2000). "Induced lactation in prepubertal Holstein heifers." J Dairy Sci 83(11): 2459-63.
Lactation was hormonally induced in six prepuberal Holstein heifers by seven daily injections of estrogen and progesterone and three injections of dexamethasone on d 18, 19, and 20, followed by twice daily hand milking beginning on d 21. Heifers were about 6 mo old and weighed 162 kg at the beginning of the experiment. Secretions were obtained from five of six of heifers, and twice daily milking continued for 75 d in three of five heifers. The volume of milk obtained on d 7 ranged from 32 to 500 ml and averaged 4.7, 4.1, and 3.7% lactose, protein, and fat, respectively. In the first natural lactation, milk yield and composition were nearly identical for controls and induced heifers. Serum alpha-lactalbumin was increased in induced heifers after treatment with dexamethasone and was highest on d 10 after onset of milking. Our data suggest that sufficient secretions for extensive biochemical testing can be obtained following hormonal induction of lactation in a majority of prepubertal heifers. Moreover, hormonal induction of lactation had no apparent effect on reproduction or first natural lactation. While it is unlikely that hormonal induction of lactation in prepubertal heifers is practical from a dairy production viewpoint, the advent of biotechnology for production of therapeutic recombinant proteins in the mammary gland of transgenic livestock has made early detection of these transgenic proteins very desirable. We conclude that induction of lactation in prepubertal heifers is a viable technique for testing the expression of mammary-linked gene constructs in transgenic cattle.
Bartha, L., G. M. Nagy, et al. (1991). "Inhibition of suckling-induced prolactin release by dexamethasone." Endocrinology 129(2): 635-40. The effect of dexamethasone (DEX) treatment (400 and 200 micrograms/kg BW 21 and 2 h before suckling stimulus, respectively) on suckling- and domperidone (DOMP)-induced PRL release was investigated in freely moving, primiparous lactating rats. DEX completely blocked suckling-induced plasma PRL release without affecting DOMP-induced release of the hormone suggesting a central action of DEX. The effect was transient because it could not be detected on the second day of testing. The effect of DEX implanted in three different brain areas on suckling- and DOMP-induced PRL release was also tested. Implants surrounding the hypothalamic paraventricular nuclei and dorsal hippocampus failed to affect PRL release induced by suckling stimulus. Surprisingly, DEX suppressed PRL release induced by suckling stimulus when it was implanted into the medial basal hypothalamus. These findings demonstrate that DEX is a potent inhibitor of the suckling-induced PRL release. They also indicate that the site of action of DEX is not at the anterior pituitary gland or the paraventricular nuclei and hippocampus because DEX treatment and DEX implants had no effect on plasma PRL levels induced by DOMP and suckling stimulus, respectively. Our data suggest that the effect of DEX is mediated through a region of the medial basal hypothalamus. The observed transient block in suckling-induced PRL release may be physiologically relevant during stress in lactating mothers for conserving pituitary stores of the hormone needed for milk production or being able to adapt to a rapid change in osmoregulation.
Basu, G. D., L. B. Pathangey, et al. (2004). "Cyclooxygenase-2 inhibitor induces apoptosis in breast cancer cells in an in vivo model of spontaneous metastatic breast cancer." Mol Cancer Res 2(11): 632-42. Cyclooxygenase-2 (COX-2) inhibitors are rapidly emerging as a new generation of therapeutic drug in combination with chemotherapy or radiation therapy for the treatment of cancer. The mechanisms underlying its antitumor effects are not fully understood and more thorough preclinical trials are needed to determine if COX-2 inhibition represents a useful approach for prevention and/or treatment of breast cancer. The purpose of this study was to evaluate the growth inhibitory mechanism of a highly selective COX-2 inhibitor, celecoxib, in an in vivo oncogenic mouse model of spontaneous breast cancer that resembles human disease. The oncogenic mice carry the polyoma middle T antigen driven by the mouse mammary tumor virus promoter and develop primary adenocarcinomas of the breast. Results show that oral administration of celecoxib caused significant reduction in mammary tumor burden associated with increased tumor cell apoptosis and decreased proliferation in vivo. In vivo apoptosis correlated with significant decrease in activation of protein kinase B/Akt, a cell survival signaling kinase, with increased expression of the proapoptotic protein Bax and decreased expression of the antiapoptotic protein Bcl-2. In addition, celecoxib treatment reduced levels of proangiogenic factor (vascular endothelial growth factor), suggesting a role of celecoxib in suppression of angiogenesis in this model. Results from these preclinical studies will form the basis for assessing the feasibility of celecoxib therapy alone or in combination with conventional therapies for treatment and/or prevention of breast cancer.
Chakriyarat, S., H. H. Head, et al. (1978). "Induction of lactation: lactational, physiological, and hormonal responses in the bovine." J Dairy Sci 61(12): 1715-24. Milk yields, physiological responses, and concentrations of plasma hormones were evaluated in 24 attempts to induce lactation in nonlactating dairy cows. Subcutaneous injections of estradiol-17beta and progesterone (10 and.25 mg/kg body weight per day) for 7 consecutive days were used. Dexamethasone injections (028 mg/kg body weight per day) on days 18 to 20 were given during 12 attempts at induction. Milking was initiated on day 21. All cows showed proestrus activity within 2 days after the first steroid injection; this subsided, then reappeared in many animals between days 16 to 20. In 14 of 24 attempts mean daily milk production was greater than 5 kg. Actual or projected 305-day lactation milk yields were between 1859 and 5354 kg. However, milk yields of seven induced cows averaged only 73% (32% to 136% range) of their previous natural lactations. Dexamethasone injections increased the number of cows that produced more than 5 kg/day; however, milk yields were not improved. Concentrations of estradiol, estrone, and progesterone in plasma were unaffected by dexamethasone, but concentrations of glucocorticoids in plasma were depressed on days 19 to 22. Concentrations of prolactin (peak and mean) in plasma for six cows each that produced greater or less than 5 kg/day did not differ. However, concentrations of prolactin increased
in the week following steroid injections (days 8 to 15) only in those cows that produced greater than 5 kg/day but were elevated in all cows during the 3rd wk.
Chen, Y. and S. R. Rittling (2003). "Novel murine mammary epithelial cell lines that form osteolytic bone metastases: effect of strain background on tumor homing." Clin Exp Metastasis 20(2): 111-20. We have developed a series of novel mammary epithelial cell lines from tumors arising in strain 129 mice, with the ultimate goal of evaluating the role of host factors in the development of bone metastases. Mammary tumors were induced in mice with subcutaneously implanted medroxyprogesterone acetate (MPA) pellets followed by administration of DMBA by oral gavage. Mammary tumor development was efficient in the 129 strain and was independent of osteopontin (OPN) expression. Epithelial cell lines were isolated from these tumors; surprisingly, these cells did not form tumors upon inoculation into the mammary fat pad of syngeneic mice, even when MPA was present. One OPN-deficient cell line was selected for further study; full transformation of these cells required expression of both polyoma middle T and activated ras. These doubly transfected cells, 1029 GP+Er3, grew in soft agar, and formed hormone-independent tumors efficiently in the mammary fat pad that spontaneously metastasized to several soft tissue sites but not to the bone. Derivatives of these cells were isolated from tumors arising in the fat pad and from a lung metastasis (r3T and r3L, respectively): these cells formed tumors more rapidly in the fat pad than the parental GP+Er3 cells. Upon left ventricle injection, the r3T and r3L cells formed osteolytic bone metastases in 129 mice, with few metastases seen in other organs. These tumors filled the marrow cavity, and caused extensive destruction of both cortical and trabecular bone. Intriguingly, in an alternative syngeneic host, (129xC57B1/6) F1, osteolytic bone metastases were not seen on x-ray; instead extensive liver metastasis was present in these mice, indicating that genetic factors in these two strains regulate tumor cell homing and distribution during metastasis. These cell lines provide an important new tool in the study of bone metastasis, particularly in elucidating the role of host factors in the development of these lesions, as the 129 mouse strain is frequently used for genetic manipulations in the mouse.
Couto, R. C., G. E. Couto, et al. (1998). "Effect of adrenalectomy and glucocorticoid therapy on lipid metabolism of lactating rats." Horm Metab Res 30(10): 614-8. Although adrenal glucocorticoids were known to be important for adequate milk production, little is known about their effects on the metabolism of mammary glands during lactation. In this study, lactating Wistar rats on the 12th day of lactation were divided in the following groups: sham-operated (SO) and adrenalectomized (ADX) receiving no treatment; SO and ADX starved for 24 h and refed
intragastrically with 2.5 ml of 50% glucose solution, 2 h before the experiment (SOR and ADXR) and ADX receiving substitute therapy with dexamethasone (ADX + DEX). Sacrifices were performed 2 days after surgery. Weight, lipid content and in vivo lipogenesis rate were evaluated in mammary gland (M.GLAND), liver, parametrial white adipose tissue (PARA) and interescapular brown adipose tissue (BAT). ATP citrate lyase activity was measured in M.GLAND, liver and PARA of SO, ADX and ADX + DEX. The rate of lipogenesis and 14CO2 production from 14C-glucose by isolated acini from M.GLAND and plasma glucose were also determined. In ADX rats, food intake, lipid content, in vivo lipogenesis rate and ATP citrate lyase activity in M.GLAND were significantly lower than those in SO rats. The M.GLAND lipogenesis rate of SOR group was similar to the value found in SO rats. In ADXR rats, the M.GLAND lipogenesis rate was not normalized. However, the therapy with DEX elevated lipid content, in vivo lipogenesis rate and ATP citrate lyase activity to levels similar to those in SO. These results suggest that the glucocorticoids are essential for the occurrence of normal lipid synthesis in M.GLAND during lactation.
Delouis, C. (1978). "Physiology of colostrum production." Ann Rech Vet 9(2): 193-203. The mammary gland growth--appearance of a lobulo-alveolar structure--, the secretion of colostrum and lactogenesis occur when precise endocrine equilibrium take place during gestation and lactation in the cow and the sow. The formation of alveoli requires hormonal sequences including first, ovarian and foetoplacental hormones--estrogens and progesterone--and, then, antepituitary--prolactin--and adrenal--corticoids--hormones. These sequences appear during pregnancy and lead to a near complete development of the mammary gland at parturition in the cow and the sow. Administrations of ovarian steroids which produce the same variations of levels of these hormones in plasma as during the pregnancy allow the lobulo-alveolar structure to develop in the non pregnant dried cow. The synthesis of specific products of milk--casseins and lactose--remains low throughout pregnancy and then increase sharply after calving or farrowing. Around parturition, the secretion of colostrum takes place when plasma levels of progesterone drop very fast and those of estrogens increase and are at the highest level observed during gestation. A few hours later, the plasma levels of prolactin and corticoids increase significantly. The colostrum secretion, the appearance of high affinity IgG1 receptors and the specific uptake of IgG1 in maternal serum coincide with a complicated hormonal environment in which a lower progesteronemia and a higher prolactinemia seem to play a major role. Estrogens-especially 17 beta-estradiol--are required for the apperance of new epithelial mammary cells which acquire specific binding sites for IgG1 later. After injections of 17 beta-estradiol and progesterone to non pregnant, dried cows, the IgG1 secretion takes place when the plasma levels of these steroids decrease. On the other hand, the secretion of colostrum is the same as in a normal parturition when calving is induced by dexamethasone or dexamethasone + estradiol benzoate injections. After parturition, there is a lower uptake of proteins from the serum when prolactin and corticoids induce the onset of copious mileticulum, of the Golgi apparatus, of mitochondria and of the appearance of a polarized structure which depress the possibilities of migration of proteins from the serum through the cell.
Feng, Z., A. Marti, et al. (1995). "Glucocorticoid and progesterone inhibit involution and programmed cell death in the mouse mammary gland." J Cell Biol 131(4): 1095-103. Milk production during lactation is a consequence of the suckling stimulus and the presence of glucocorticoids, prolactin, and insulin. After weaning the glucocorticoid hormone level drops, secretory mammary epithelial cells die by programmed cell death and the gland is prepared for a new pregnancy. We studied the role of steroid hormones and prolactin on the mammary gland structure, milk protein synthesis, and on programmed cell death. Slow-release plastic pellets containing individual hormones were implanted into a single mammary gland at lactation. At the same time the pups were removed and the consequences of the release of hormones were investigated histologically and biochemically. We found a local inhibition of involution in the vicinity of deoxycorticosterone- and progesterone-release pellets while prolactin-release pellets were ineffective. Dexamethasone, a very stable and potent glucocorticoid hormone analogue, inhibited involution and programmed cell death in all the mammary glands. It led to an accumulation of milk in the glands and was accompanied by an induction of protein kinase A, AP-1 DNA binding activity and elevated c-fos, junB, and junD mRNA levels. Several potential target genes of AP-1 such as stromelysin-1, c-jun, and SGP-2 that are induced during normal involution were strongly inhibited in dexamethasone-treated animals. Our results suggest that the cross-talk between steroid hormone receptors and AP-1 previously described in cells in culture leads to an impairment of AP-1 activity and to an inhibition of involution in the mammary gland implying that programmed cell death in the postlactational mammary gland depends on functional AP-1.
Fowler, P. A., C. H. Knight, et al. (1991). "In-vivo magnetic resonance imaging studies of mammogenesis in non-pregnant goats treated with exogenous steroids." J Dairy Res 58(2): 151-7. Mammogenesis and lactation were induced in five multiparous, non-pregnant goats by treatment with oestrogen and progesterone for 11 d, followed by dexamethasone for 3 d. Reserpine was administered during the last 5 d. All five goats lactated, although milk yield was less than had been achieved in previous natural lactations. Mammary development was assessed in vivo, using magnetic resonance imaging. Although parenchyma volume increased by more than 6-fold overall, only 25% of this increase occurred during steroid treatment. Most development took place after the cessation of treatment, when milking commenced. Maximum size was not achieved until week 8 of the induced lactation, and was only 70% of normal parenchyma volume. After 18 weeks lactation the activities of three key milk synthetic enzymes were very similar to values previously found in natural lactations, and secretion efficiency (milk production per unit volume of parenchyma) was
also similar to that of natural lactations. We conclude that the lower than normal milk yields were associated with incomplete proliferation of mammary tissue, rather than inadequate differentiation of individual secretory cells.
Green, J. E. and T. Hudson (2005). "The promise of genetically engineered mice for cancer prevention studies." Nat Rev Cancer 5(3): 184-98. Sophisticated genetic technologies have led to the development of mouse models of human cancers that recapitulate important features of human oncogenesis. Many of these genetically engineered mouse models promise to be very relevant and relatively rapid systems for determining the efficacy of chemopreventive agents and their mechanisms of action. The validation of such models for chemoprevention will help the selection of appropriate agents for large-scale clinical trials and allow the testing of combination therapies.
Head, H. H., S. Chakriyarat, et al. (1982). "Induction of lactation: comparison of injections of estradiol-17 beta and progesterone for 7 or 21 days on prolactin response to thyrotropin releasing hormone and milk yield in dairy cattle." J Dairy Sci 65(6): 927-36. Subcutaneous injections of estradiol-17 beta and progesterone (10 and.25 mg/kg of body weight) for 7 (group I) or 21 (II) days were used. Dexamethasone (028 mg/kg of body weight per day) or adrenocorticotropin (200 IU per day) was injected into cows in each group on days 18 to 20 (I) or 32 to 34 (II). Additionally, 100 mug of thyrotropin releasing hormone was injected intravenously on days 1, 7, 17 (I) or 1, 7, and 31 (II). Milking was initiated on days 21 (I) or 35 (II). Overall 13 of 14 cows had mean daily yields of milk greater than 5 kg; 12 had 305-day lactations. Yields of milk in cows injected for 21 days were greater on day 1 and increased more rapidly until peak was reached at 10 wk; daily mean production throughout lactation was greater (14.3 versus 10.1 kg) than for cows injected for 7 days. Lactation curves pooled within cow within treatment differed. Concentrations of estradiol, estrone and progesterone increased during steroid injections and were 2- to 3-fold higher on day 21 in II than on day 7 (I or II), but concentrations of prolactin and total glucocorticoids in plasma did not differ during this time. The quantity of prolactin released in response to injection of thyrotropin releasing hormone was greater 10 days after steroid injections than before or during steroid injections. Preinjection concentrations of prolactin were correlated with magnitude of postinjection response to thyrotropin releasing hormone, but response was not correlated with concentrations of steroids in plasma on day of injection.
Hennighausen, L. G. and A. E. Sippel (1982). "Mouse whey acidic protein is a novel member of the family of 'four-disulfide core' proteins." Nucleic Acids Res 10(8): 2677-84. Unlike in other mammalian species, the major whey protein in mouse is not alpha-lactalbumin, but a cysteine rich, acidic protein with a molecular weight of 14.0 kDa. We have deduced the amino acid sequence of this mouse acidic of whey protein from the nucleotide sequence of cloned cDNA. The positions of the half cysteines suggest that mouse whey acidic protein (WAP) is a two domain protein, very similar in structure to the plant lectin wheat germ agglutinin and the hypothalamic carrier protein neurophysin. Kogai T, Kanamoto Y, Li AI, Che LH, Ohashi E, Taki K, Chandraratna RA, Saito T, Brent GA) Differential regulation of sodium/iodide symporter gene expression by nuclear receptor ligands in MCF-7 breast cancer cells.Endocrinology. 2005 Jul;146(7):3059-69. Molecular Endocrinology Laboratory, Veterans Affairs Greater Los Angeles Healthcare System, David Geffen School of Medicine at the University of California, Los Angeles, CA 90073, USA. The sodium/iodide symporter (NIS) mediates iodide uptake in lactating breast tissue and is expressed in some breast cancers. We have previously demonstrated that all-trans retinoic acid (tRA) stimulates NIS gene expression and the selective cytotoxic effect of beta-emitting radioiodide-131 ((131)I) in both in vitro and in vivo MCF-7 breast cancer cell systems. We studied the ability of natural and synthetic retinoids, in combination with other nuclear receptor ligands, to achieve greater and more sustained induction of NIS in MCF-7 cells and enhance (131)I-mediated cytotoxicity. Selective stimulation of retinoic acid receptor (RAR) beta/gamma produced marked NIS induction; and selective stimulation of RARalpha, RARgamma, or retinoid X receptor produced more modest induction. Maximal NIS induction was seen with 9-cis retinoic acid and AGN190168, a RAR beta/gamma-agonist. Dexamethasone (Dex), but not the other nuclear receptor ligands, in combination with tRA synergistically induced iodide uptake and NIS mRNA expression, predominantly by prolonging NIS mRNA half-life. The addition of Dex reduced the EC(50) of tRA for NIS stimulation to approximately 7%, such that 10(-7) m tRA with addition of Dex enhanced iodide uptake and selective cytotoxicity of (131)I greater than 10(-6) m tRA alone. AGN190168 combined with Dex synergistically increased iodide uptake and significantly prolonged induction (5 d) of iodide uptake compared with that induced by the combination of tRA/Dex or 9-cis retinoic acid/Dex. The addition of Dex reduced the effective dose of retinoid and prolonged the induction of NIS, especially with AGN190168, suggesting higher efficacy of (131)I after combination treatment.
Kort, W. J., I. M. Weijma, et al. (1987). "Is the 7,12-dimethylbenz[a]anthracene-induced rat mammary tumor model suitable as a preclinical model to study mammary tumor malignancy?" Cancer Invest 5(5): 443-7. To study the biological characteristics of 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors in rats, 20 Sprague Dawley female rats received a single oral dose of 5 mg of this carcinogen. During the 35-week observation time 78 primary tumors were removed. While in most cases the primary tumor could be removed completely, 7 out of 20 animals eventually had to be sacrificed for inoperable local recurrence of the primary tumor. Notwithstanding, the long period of time given for tumor metastases to develop (mean time between tumor removal and termination was 18.5 weeks), tumor spread either to lungs or regional lymph nodes could not be established. This relatively benign behavior of the tumor was in contrast with the morphological characteristics of the tumor, which uniformly showed the features of adenocarcinomas. The difference in biological behavior between DMBA-induced mammary tumors in rats and malignant mammary tumors in humans suggests that as a model this system is of limited value for investigations of mechanisms of malignant behavior of human tumors.
Liu, R. H., J. Liu, et al. (2005). "Apples prevent mammary tumors in rats." J Agric Food Chem 53(6): 2341-3. Regular consumption of fruits and vegetables has been consistently shown to be associated with reduced risk of developing chronic diseases such as cancer and cardiovascular disease. Apples are commonly consumed and are the major contributors of phytochemicals in human diets. It was previously reported that apple extracts exhibit strong antioxidant and antiproliferative activities and that the major part of total antioxidant activity is from the combination of phytochemicals. Phytochemicals, including phenolics and flavonoids, are suggested to be the bioactive compounds contributing to the health benefits of apples. Here it is shown that whole apple extracts prevent mammary cancer in a rat model in a dose-dependent manner at doses comparable to human consumption of one, three, and six apples a day. This study demonstrated that whole apple extracts effectively inhibited mammary cancer growth in the rat model; thus, consumption of apples may be an effective strategy for cancer protection.
MacEwen, E. G. (1990). "Spontaneous tumors in dogs and cats: models for the study of cancer biology and treatment." Cancer Metastasis Rev 9(2): 125-36. Spontaneous tumors in dogs and cats are appropriate and valid model tumor systems available for testing cancer therapeutic agents or studying cancer biology. The pet population is a vastly underutilized resource of animals available for study. Dogs and cats develop
spontaneous tumors with histopathologic and biologic behavior similar to tumors that occur in humans. The tumors with potential relevance for human cancer biology include osteosarcoma, mammary carcinoma, oral melanoma, oral squamous cell carcinoma, nasal tumors, lung carcinoma, soft tissue sarcomas, and malignant non-Hodgkin's lymphoma. Canine osteosarcoma is a malignant aggressive bone tumor with a 90% metastasis rate after surgical amputation. Its predictable metastatic rate and pattern and its relative resistance to chemotherapy make this tumor particularly attractive for studying anti-metastasis approaches. Canine and feline malignant mammary tumors are fairly common in middle-aged animals and have a metastatic pattern similar to that in women; that is, primarily to regional lymph nodes and lungs. Chemotherapy has been minimally effective, and these tumors may be better models for testing biological response modifiers. Oral tumors, especially melanomas, are the most common canine malignant tumor in the oral cavity. Metastasis is frequent, and the response to chemotherapy and radiation has been disappointing. This tumor can be treated with anti-metastatic approaches or biological response modifiers. Squamous cell carcinomas, especially in the gum, are excellent models for radiation therapy studies. Nasal carcinomas are commonly treated with radiation therapy. They tend to metastasize slowly, but have a high local recurrence rate. This tumor is suitable for studying radiation therapy approaches. Primary lung tumors and soft tissue sarcomas are excellent models for studying combined modality therapy such as surgery with chemotherapy or biological response modifiers. Finally, non-Hodgkin's lymphoma is a common neoplastic process seen in the dog. These tumors respond to combination chemotherapy and have great potential as a model for newer chemotherapeutic agents and biological response modifiers. This paper will further elaborate on the relative merits of each tumor type as a model for human cancer therapy and biology.
Marte, B. M., M. Jeschke, et al. (1995). "Neu differentiation factor/heregulin modulates growth and differentiation of HC11 mammary epithelial cells." Mol Endocrinol 9(1): 14-23. The HC11 mouse mammary epithelial cell line has proven to be a valuable in vitro model to study the roles of peptide factors and hormones involved in the growth and differentiation of mammary cells. Treatment of HC11 cells with the lactogenic hormones, dexamethasone, insulin, and PRL (DIP), leads to cellular differentiation and production of the milk protein beta-casein. We have analyzed the effects of Neu differentiation factor (NDF)/heregulin, a newly described activating ligand for erbB-2 and other members of the epidermal growth factor (EGF) receptor family, on cell growth and the expression of milk proteins in HC11 cells. In these cells, NDF induces tyrosine phosphorylation of erbB-2 and erbB-3. Both NDF and EGF stimulate HC11 cell proliferation and promote the responsiveness of HC11 cells to lactogenic hormones. NDF induces the expression of a 22-kilodalton milk protein. This protein is up-regulated by other factors, including dexamethasone, EGF, and basic fibroblast growth factor, and is controlled in a manner distinct from that of beta-casein. Like EGF, NDF inhibits the DIP-induced expression of beta-casein at the level of transcription. The inhibition is due to the negative effect of NDF on the
activation of mammary gland factor (MGF/Stat5), a member of the Stat family of transcription factors, which is essential for beta-casein gene expression.
Marte, B. M., T. Meyer, et al. (1994). "Protein kinase C and mammary cell differentiation: involvement of protein kinase C alpha in the induction of beta-casein expression." Cell Growth Differ 5(3): 239-47. Treatment of HC11 mouse mammary epithelial cells with the lactogenic hormones dexamethasone, insulin, and prolactin (DIP) leads to cellular differentiation and production of the milk protein beta-casein. The following experimental evidence suggests the involvement of protein kinase C (PKC) in DIP induced signal transduction. Down-regulation of PKC by 12-O-tetradecanoylphorbol-13-acetate or addition of CGP 41251, a selective inhibitor of PKC, inhibited beta-casein protein expression induced by DIP in HC11 cells. This inhibition occurs at the level of transcription, since the DIP mediated activation of a beta-casein promoter-luciferase reporter construct or of mammary gland specific factor (MGF), an essential transcription factor for beta-casein promoter activity, was also inhibited by CGP 41251. Inhibition or down-regulation of PKC reduced the activation of MGF by prolactin as well. PKC-alpha, the only conventional PKC isoform expressed in HC11 cells, is most likely involved in the DIP induced beta-casein expression. (a) Only PKC-alpha and PKC-epsilon are down-regulated by 12-O-tetradecanoylphorbol-13-acetate whereas PKC-delta and PKC-zeta are not. (b) Of the PKC isoforms expressed in HC11 cells, CGP 41251 inhibits PKC-alpha more potently than PKC-delta, PKC-epsilon, and PKC-zeta. The IC50 for the inhibition of beta-casein synthesis, MGF activation, and beta-casein promoter activity by CGP 41251 correlated well with the IC50 of PKC-alpha inhibition. (c) Finally, only PKC-alpha translocated to membrane fractions after DIP or prolactin treatment. Taken together, these data indicate that PKC-alpha plays an important role in the signaling pathway activated by prolactin during beta-casein induction.
Mikosz, C. A., D. R. Brickley, et al. (2001). "Glucocorticoid receptor-mediated protection from apoptosis is associated with induction of the serine/threonine survival kinase gene, sgk-1." J Biol Chem 276(20): 16649-54. We previously demonstrated that activation of the glucocorticoid receptor (GR) initiates an antiapoptotic signal in the immortalized human mammary epithelial cell line MCF10A that is dependent on the GR's transcriptional activity. In this study, we show that the survival role of GR activation extends to protecting human breast cancer cells undergoing apoptosis after growth factor deprivation. Serum and glucocorticoid-regulated kinase-1 (sgk), a gene previously identified as a direct transcriptional target of the activated GR in a rat mammary tumor cell line, was rapidly induced after GR activation in human mammary epithelial cells. Furthermore, in the
absence of all growth factors, ectopic sgk expression inhibited apoptosis, suggesting that SGK is a survival kinase. Finally, kinasedead SGK expression inhibited the protection from apoptosis usually seen after GR activation. These findings suggest that SGK is an important downstream target of GR-mediated survival signaling and that it is distinct from other survival kinases because it can be primarily regulated at the level of transcription.
Niermann, G. L. and G. C. Buehring (1997). "Hormone regulation of bovine leukemia virus via the long terminal repeat." Virology 239(2): 249-58. The hormone regulation of viruses has been of great interest since the discovery of glucocorticoid stimulation of mouse mammary tumor virus via a hormone response element in the viral long terminal repeat (LTR) promoter region. This report describes the investigation of the hormone responsiveness of bovine leukemia virus (BLV), an oncogenic retrovirus that infects dairy and beef cattle worldwide. It is a member of the human T cell leukemia (HTLV)/BLV group of retroviruses, which encode a protein, Tax, that is essential for regulating transcription of their own proviruses and for transforming host cells. We investigated the responsiveness of BLV to the hormones 17 betaestradiol, progesterone, prolactin, insulin, and dexamethasone, a potent glucocorticoid. Only dexamethasone, in combination with insulin or insulin/prolactin, consistently stimulated BLV expression, as measured by reverse transcriptase activity, RNA blot hybridization (Northern blots), and CAT (chloramphenicol acetyltransferase) reporter assays of cell lines transiently or stably transfected with the BLV LTR. This effect required the presence of glucocorticoid receptors and Tax. This is the first report of hormone responsiveness in a virus of the HTLV/BLV group.
Peace, B. E., K. Toney-Earley, et al. (2005). "Ron receptor signaling augments mammary tumor formation and metastasis in a murine model of breast cancer." Cancer Res 65(4): 1285-93. The tyrosine kinase receptor Ron has been implicated in several types of cancer, including overexpression in human breast cancer. This is the first report describing the effect of Ron signaling on tumorigenesis and metastasis in a mouse model of breast cancer. Mice with a targeted deletion of the Ron tyrosine kinase signaling domain (TK-/-) were crossed to mice expressing the polyoma virus middle T antigen (pMT) under the control of the mouse mammary tumor virus promoter. Both pMT-expressing wild-type control (pMT+/- TK+/+) and pMT+/- TK-/- mice developed mammary tumors and lung metastases. However, a significant decrease in mammary tumor initiation and growth was found in the pMT+/- TK-/- mice compared with controls. An examination of mammary tumors showed that there was a significant decrease in microvessel density, significantly decreased cellular proliferation, and a significant increase in terminal
deoxynucleotidyl transferase-mediated nick end labeling-positive staining in mammary tumor cells from the pMT+/- TK-/- mice compared with the pMT+/- TK+/+ mice. Biochemical analyses on mammary tumor lysates showed that whereas both the pMT-expressing TK+/+ and TK-/- tumors have increased Ron expression compared with normal mammary glands, the pMT-expressing TK-/- tumors have deficits in mitogen-activated protein kinase and AKT activation. These results indicate that Ron signaling synergizes with pMT signaling to induce mammary tumor formation, growth, and metastasis. This effect may be mediated in part through the regulation of angiogenesis and through proliferative and cell survival pathways regulated by mitogen-activated protein kinase and AKT.
Waters, D. J., A. Honeckman, et al. (1998). "Skeletal metastasis in feline mammary carcinoma: case report and literature review." J Am Anim Hosp Assoc 34(2): 103-8. Despite the highly malignant nature of feline mammary carcinoma, few cases of skeletal metastasis have been reported. In this paper, a case of feline mammary carcinoma with skeletal metastasis to a distal limb is presented. The pertinent literature on feline mammary carcinoma and bone metastases is reviewed. Although the metastases of carcinomas in dogs and humans usually exhibit a proximal skeletal distribution, cats are more likely to develop distal extremity lesions. Clinicians need to have an index of suspicion that skeletal metastases may be responsible for lameness in elderly cats. Further investigation of the comparative aspects of bone metastases in cats and other species may elucidate the factors that regulate the development of skeletal metastases.
Wu, W., S. Chaudhuri, et al. (2004). "Microarray analysis reveals glucocorticoid-regulated survival genes that are associated with inhibition of apoptosis in breast epithelial cells." Cancer Res 64(5): 1757-64. Activation of the glucocorticoid receptor (GR) results in diverse physiological effects depending on cell type. For example, glucocorticoids (GC) cause apoptosis in lymphocytes but can rescue mammary epithelial cells from growth factor withdrawal-induced death. However, the molecular mechanisms of GR-mediated survival remain poorly understood. In this study, a large-scale oligonucleotide screen of GRregulated genes was performed. Several of the genes that were found to be induced 30 min after GR activation encode proteins that function in cell survival signaling pathways. We also demonstrate that dexamethasone pretreatment of breast cancer cell lines inhibits chemotherapyinduced apoptosis in a GR-dependent manner and is associated with the transcriptional induction of at least two genes identified in our screen, serum and GC-inducible protein kinase-1 (SGK-1) and mitogen-activated protein kinase phosphatase-1 (MKP-1). Furthermore, GC treatment alone or GC treatment followed by chemotherapy increases both SGK-1 and MKP-1 steady-state protein levels. In the absence of
GC treatment, ectopic expression of SGK-1 or MKP-1 inhibits chemotherapy-induced apoptosis, suggesting a possible role for these proteins in GR-mediated survival. Moreover, specific inhibition of SGK-1 or MKP-1 induction by the introduction of SGK-1- or MKP-1-small interfering RNA reversed the anti-apoptotic effects of GC treatment. Taken together, these data suggest that GR activation in breast cancer cells regulates survival signaling through direct transactivation of genes that encode proteins that decrease susceptibility to apoptosis. Given the widespread clinical administration of dexamethasone before chemotherapy, understanding GR-induced survival mechanisms is essential for achieving optimal therapeutic responses.
Wu, W., T. Pew, et al. (2005). "Glucocorticoid receptor-induced MAPK phosphatase-1 (MPK-1) expression inhibits paclitaxel-associated MAPK activation and contributes to breast cancer cell survival." J Biol Chem 280(6): 4117-24. Glucocorticoid receptor (GR) activation has recently been shown to inhibit apoptosis in breast epithelial cells. We have previously described a group of genes that is rapidly up-regulated in these cells following dexamethasone (Dex) treatment. In an effort to dissect the mechanisms of GR-mediated breast epithelial cell survival, we now examine the molecular events downstream of GR activation. Here we show that GR activation leads to both the rapid induction of MAPK phosphatase-1 (MKP-1) mRNA and its sustained expression. Induction of the MKP-1 protein in the MCF10A-Myc and MDA-MB-231 breast epithelial cell lines was also seen. Paclitaxel treatment resulted in MAPK activation and apoptosis of MDA-MB-231 breast cancer cells, and both processes were inhibited by Dex pretreatment. Furthermore, induction of MKP-1 correlated with the inhibition of extracellular signal-regulated kinase (ERK1/2) and c-Jun N-terminal kinase (JNK) activity, whereas p38 activity was minimally affected. Blocking Dex-induced MKP-1 induction using small interfering RNA increased ERK1/2 and JNK phosphorylation and decreased cell survival. ERK1/2 and JNK inactivation was associated with Ets-like transcription factor-1 (ELK-1) dephosphorylation. To explore the gene expression changes that occur downstream of ELK-1 dephosphorylation, we used a combination of temporal gene expression data and promoter element analyses. This approach revealed a previously unrecognized transcriptional target of ELK-1, the human tissue plasminogen activator (tPA). We verified the predicted ELK-1--> tPA transcriptional regulatory relationship using a luciferase reporter assay. We conclude that GR-mediated MAPK inactivation contributes to cell survival and that the potential transcriptional targets of this inhibition can be identified from large scale gene array analysis. Permalink Archive Library of Congress: http://web.archive.org/web/*/http://www.erieping.de/answer4.htm (not available?)
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