Milchbildende Hormone und Brustkrebs von Elisabeth Rieping

8/3/2019 Milchbildende Hormone und Brustkrebs von Elisabeth Rieping

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Milchbildende Hormone und Brustkrebs

Stand / Letzte Aktualisierung durch ElisabethRieping 22.11.2006

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Stichworte: Virus, Brustkrebs als Viruskrankheit, Onkogene,Cortisol, Cortison, Infektionswege, Milchbildung, Stillen

Forum

Zu Entstehung des epidemischen Brustkrebszu

Dexamethasone

Die laktogenen Hormone

Das wirksamste Hormon zur Aktivierung des Mausmamma-Tumor-Virus war immer das Dexamethason,

das auch unter dem Handelsnamen Fortecortin bekannt ist. Es gehrt zu den Glucocorticoiden. Das verursachteallerdings Verwunderung. Denn als man die Wirkung des Dexamethasons auf die Aktivierung des Mausmamma-Tumor-Virus erkannte, war es nicht bekannt, dass Glucocorticoide zu den Stillhormonen gehren und in derStillzeit die Milchproduktion aufrecht erhalten.

Vermutlich ist das in der Humanmedizin immer noch nicht sehr bekannt, denn die meisten Informationen darberfinden sich in Zeitschriften der Milchwirtschaft.

Anwendung des Fortecortins (Dexamethasons) in der MedizinBei der Chemotherapie von Krebserkrankungen wird es zur Unterdrckung von belkeit und Erbrecheneingesetzt. Wenn man bedenkt, dass dadurch vielleicht Tumorviren gefrdert werden knnen, ist das nicht ganzunbedenklich (Wu, Chaudhuri et al. 2004).

Bei der Rheumatischen Arthritis wird es in das Gelenk installiert, um den entzndlichen Prozess zu unterdrcken.
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Auch bei entzndlichen Prozessen des Auges wird es benutzt. Zuerst wurde Cortison aber als Gegenspieler desInsulins in Bezug auf den Blutzuckerspiegel bekannt. Whrend Insulin die Glucose aus dem Blut in die Zellenschickt, sorgen seine Gegenspieler, die Cortisone, fr die Erhhung des Glucosespiegels im Blut, wie wir schon inder Schule gelernt haben. So wird unter Stress Cortison ausgeschttet, das den Blutzucker erhht, damit man zum

Beispiel Energie zum Weglaufen oder Kmpfen hat.

Wirkung auf die MilchproduktionAuf die Milchproduktion hat das Dexamethasone kurzfristig einen dmpfenden Effekt. Im Stress wird es kurzunterdrckt (Andersson and Olsson 1984), weil in solchen Situationen ein hoher Blutzuckerspiegel wichtiger ist,als die Suglingsernhrung. Mglicherweise passiert das durch die Behinderung der durch Saugen ausgelstenProlaktinausschttung (Bartha, Nagy et al. 1991).

Die Senkung der Milchproduktion dauert nicht lange an und da Glucocorticoide oft stressbedingt ausgeschttetwerden, kann man annehmen, dass diese Wirkung die Milchproduktion vielleicht nur in kurzen Momenten derGefahr, Flucht vor einem Raubtier oder in hnlichen Situationen unterdrcken soll. Denn abgesehen von derkurzen Unterdrckung der Milchproduktion bei Stress gehren die Cortisone zu den laktogenen Hormonen,also Milch frdernden Hormonen, was in der Milchwirtschaft wichtig zu wissen ist.

So kann man mit Dexamethason, Insulin und Prolaktin, den sogenannten laktogenen, also Milch frderndenHormonen, die Differenzierung und die Casein-Produktion in Brustdrsen-Epithelzellen von Musen (Marte,Meyer et al. 1994, Marte, Jeschke et al. 1995) und vermutlich auch in anderen Tieren auslsen.

Auch die Lipogenese in der Brustdse wird durch Dexamethason gefrdert (Couto, Couto et al. 1998).

In der Stillphase wird die Milchproduktion durch den Saugreiz und die Anwesenheit der drei Stillhormone

aufrechterhalten. In Gegenwart von Dexamethason und Insulin kann sich die Brustdrse nach dem Abstillen nichtzurckbilden (Feng, Marti et al. 1995).

Die hormonelle Steuerung der Virusaktivierung durch StillhormoneDa die Zeit der Milchproduktion die gnstigste fr die Weitergabe eines Milchvirus ist, wundert es nicht, dass
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diese Viren ber einen Cortison-aktivierbaren Promotor gerade in dieser Zeit aktiviert werden. Aber auch schonvor der Stillzeit wirkt Dexamethason auf die Brustentwicklung ein.

So kann mit einer Kombination aus strogen, Progesteron und Dexamethason schon vor deren Pubertt dieMilchproduktion in Rindern ausgelst 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 desBrustdrsengewebes bewirken, ohne das eine Schwangerschaft vorausgegangen ist.

Die Entwicklung der Epithelzellen zu aktiven Brustdrsenzellen und die sptere Milchproduktion sind zweiProzesse, die beide ntig sind, um Milch zu produzieren und sie sind beide abhngig von den laktogenenHormonen. Die Aktivierung der mit der Milch transportierten Viren durch die gleichen Hormone (Niermann andBuehring 1997) sorgt dafr, dass sie mit der Milch weitergegeben werden und so in den nchsten Wirt gelangenknnen. Das ist wahrscheinlich der natrliche Verbreitungsmodus dieser Viren wie BLV, MMTV, HTLV undHIV.

Die Vorteile des durch laktogene Hormone aktivierbaren Promotors fr die milchbertragenen VirenForum Es gibt viele Mglichkeiten fr den Virus, in einen neuen Wirt zu gelangen. Zum Beispiel durch den

Geschlechtsverkehr ber einen Transport mit dem Sperma, durch verseuchte Blutprodukte bei Transfusionen undhnliche Vorgnge. Auch das Essen eines infizierten Tieres knnte zur bertragung fhren. So sollen zumBeispiel die Aidsviren von infizierten Affen, in denen sie keine Krankheit verursachen, in die Menschen gelangtsein.

Der durch Stillhormone aktivierbare Promotor spricht aber dafr, dass der Weg ber die Milch fr das Virusvermutlich einige Vorteile bietet. Einer dieser Vorteile knnte in der Infektion zu einem frhen Zeitpunkt imLaufe des Lebens liegen, in dem der neue Wirt das Virus noch nicht als fremd erkennt und so keine

Immunantwort gegen das infektise Agens ausgelst wird.

zu Brustkrebs bei Tierenzu Dexamethasone

Mehr Literatur
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Andersson, L. and T. Olsson (1984). "The effect of two glucocorticoids on plasma glucose and milk production in healthy cows and the therapeuticeffect 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 significantlyincreased 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 therapeuticeffect in bovine ketosis of the two preparations was measured by means of analysis of acetone plus acetoacetate in milk sampled dailyduring eight days post treatment. Acetone plus acetoacetate in milk from cows given dexamethasone phosphate + dexamethasonephenylpropionate (n = 11) decreased to normal levels and from the fourth day after treatment was significantly lower than in cows givendexamethasone 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 threeinjections of dexamethasone on d 18, 19, and 20, followed by twice daily hand milking beginning on d 21. Heifers were about 6 mo old andweighed 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 ofmilking. Our data suggest that sufficient secretions for extensive biochemical testing can be obtained following hormonal induction oflactation in a majority of prepubertal heifers. Moreover, hormonal induction of lactation had no apparent effect on reproduction or firstnatural lactation. While it is unlikely that hormonal induction of lactation in prepubertal heifers is practical from a dairy productionviewpoint, the advent of biotechnology for production of therapeutic recombinant proteins in the mammary gland of transgenic livestock hasmade early detection of these transgenic proteins very desirable. We conclude that induction of lactation in prepubertal heifers is a viabletechnique 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) onsuckling- and domperidone (DOMP)-induced PRL release was investigated in freely moving, primiparous lactating rats. DEX completely


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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 brainareas on suckling- and DOMP-induced PRL release was also tested. Implants surrounding the hypothalamic paraventricular nuclei anddorsal hippocampus failed to affect PRL release induced by suckling stimulus. Surprisingly, DEX suppressed PRL release induced bysuckling 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 theparaventricular nuclei and hippocampus because DEX treatment and DEX implants had no effect on plasma PRL levels induced by DOMPand 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 forconserving 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 spontaneousmetastatic 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 orradiation 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 vivooncogenic mouse model of spontaneous breast cancer that resembles human disease. The oncogenic mice carry the polyoma middle Tantigen driven by the mouse mammary tumor virus promoter and develop primary adenocarcinomas of the breast. Results show that oraladministration of celecoxib caused significant reduction in mammary tumor burden associated with increased tumor cell apoptosis anddecreased proliferation in vivo. In vivo apoptosis correlated with significant decrease in activation of protein kinase B/Akt, a cell survivalsignaling kinase, with increased expression of the proapoptotic protein Bax and decreased expression of the antiapoptotic protein Bcl-2. Inaddition, celecoxib treatment reduced levels of proangiogenic factor (vascular endothelial growth factor), suggesting a role of celecoxib insuppression of angiogenesis in this model. Results from these preclinical studies will form the basis for assessing the feasibility of celecoxibtherapy 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 Sci61(12): 1715-24.


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Milk yields, physiological responses, and concentrations of plasma hormones were evaluated in 24 attempts to induce lactation innonlactating dairy cows. Subcutaneous injections of estradiol-17beta and progesterone (10 and.25 mg/kg body weight per day) for 7consecutive days were used. Dexamethasone injections (028 mg/kg body weight per day) on days 18 to 20 were given during 12 attempts atinduction. 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 5kg/day; however, milk yields were not improved. Concentrations of estradiol, estrone, and progesterone in plasma were unaffected bydexamethasone, but concentrations of glucocorticoids in plasma were depressed on days 19 to 22. Concentrations of prolactin (peak andmean) in plasma for six cows each that produced greater or less than 5 kg/day did not differ. However, concentrations of prolactin increasedin 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 cowsduring the 3rd wk.

Chen, Y. and S. R. Rittling (2003). "Novel murine mammary epithelial cell lines that form osteolytic bone metastases: effect of strain backgroundon 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 ofevaluating the role of host factors in the development of bone metastases. Mammary tumors were induced in mice with subcutaneouslyimplanted medroxyprogesterone acetate (MPA) pellets followed by administration of DMBA by oral gavage. Mammary tumor developmentwas 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 Tand activated ras. These doubly transfected cells, 1029 GP+Er3, grew in soft agar, and formed hormone-independent tumors efficiently inthe mammary fat pad that spontaneously metastasized to several soft tissue sites but not to the bone. Derivatives of these cells were isolatedfrom tumors arising in the fat pad and from a lung metastasis (r3T and r3L, respectively): these cells formed tumors more rapidly in the fatpad than the parental GP+Er3 cells. Upon left ventricle injection, the r3T and r3L cells formed osteolytic bone metastases in 129 mice, withfew metastases seen in other organs. These tumors filled the marrow cavity, and caused extensive destruction of both cortical and trabecularbone. Intriguingly, in an alternative syngeneic host, (129xC57B1/6) F1, osteolytic bone metastases were not seen on x-ray; instead extensiveliver metastasis was present in these mice, indicating that genetic factors in these two strains regulate tumor cell homing and distributionduring metastasis. These cell lines provide an important new tool in the study of bone metastasis, particularly in elucidating the role of hostfactors in the development of these lesions, as the 129 mouse strain is frequently used for genetic manipulations in the mouse.


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Couto, R. C., G. E. Couto, et al. (1998). "Effect of adrenalectomy and glucocorticoid therapy on lipid metabolism of lactating rats." Horm MetabRes 30(10): 614-8.

Although adrenal glucocorticoids were known to be important for adequate milk production, little is known about their effects on themetabolism 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 refedintragastrically with 2.5 ml of 50% glucose solution, 2 h before the experiment (SOR and ADXR) and ADX receiving substitute therapywith dexamethasone (ADX + DEX). Sacrifices were performed 2 days after surgery. Weight, lipid content and in vivo lipogenesis rate wereevaluated 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 14CO2production from 14C-glucose by isolated acini from M.GLAND and plasma glucose were also determined. In ADX rats, food intake, lipidcontent, in vivo lipogenesis rate and ATP citrate lyase activity in M.GLAND were significantly lower than those in SO rats. The M.GLANDlipogenesis 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 inSO. 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 preciseendocrine equilibrium take place during gestation and lactation in the cow and the sow. The formation of alveoli requires hormonalsequences including first, ovarian and foetoplacental hormones--estrogens and progesterone--and, then, antepituitary--prolactin--andadrenal--corticoids--hormones. These sequences appear during pregnancy and lead to a near complete development of the mammary gland atparturition in the cow and the sow. Administrations of ovarian steroids which produce the same variations of levels of these hormones inplasma as during the pregnancy allow the lobulo-alveolar structure to develop in the non pregnant dried cow. The synthesis of specificproducts of milk--casseins and lactose--remains low throughout pregnancy and then increase sharply after calving or farrowing. Aroundparturition, the secretion of colostrum takes place when plasma levels of progesterone drop very fast and those of estrogens increase and areat the highest level observed during gestation. A few hours later, the plasma levels of prolactin and corticoids increase significantly. Thecolostrum secretion, the appearance of high affinity IgG1 receptors and the specific uptake of IgG1 in maternal serum coincide with acomplicated 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 IgG1later. After injections of 17 beta-estradiol and progesterone to non pregnant, dried cows, the IgG1 secretion takes place when the plasmalevels of these steroids decrease. On the other hand, the secretion of colostrum is the same as in a normal parturition when calving is induced


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by dexamethasone or dexamethasone + estradiol benzoate injections. After parturition, there is a lower uptake of proteins from the serumwhen prolactin and corticoids induce the onset of copious mileticulum, of the Golgi apparatus, of mitochondria and of the appearance of apolarized 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. Afterweaning the glucocorticoid hormone level drops, secretory mammary epithelial cells die by programmed cell death and the gland is preparedfor a new pregnancy. We studied the role of steroid hormones and prolactin on the mammary gland structure, milk protein synthesis, and onprogrammed cell death. Slow-release plastic pellets containing individual hormones were implanted into a single mammary gland atlactation. At the same time the pups were removed and the consequences of the release of hormones were investigated histologically andbiochemically. We found a local inhibition of involution in the vicinity of deoxycorticosterone- and progesterone-release pellets whileprolactin-release pellets were ineffective. Dexamethasone, a very stable and potent glucocorticoid hormone analogue, inhibited involutionand programmed cell death in all the mammary glands. It led to an accumulation of milk in the glands and was accompanied by an inductionof 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-treatedanimals. Our results suggest that the cross-talk between steroid hormone receptors and AP-1 previously described in cells in culture leads toan impairment of AP-1 activity and to an inhibition of involution in the mammary gland implying that programmed cell death in thepostlactational 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 withexogenous 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 thanhad been achieved in previous natural lactations. Mammary development was assessed in vivo, using magnetic resonance imaging. Althoughparenchyma volume increased by more than 6-fold overall, only 25% of this increase occurred during steroid treatment. Most developmenttook place after the cessation of treatment, when milking commenced. Maximum size was not achieved until week 8 of the inducedlactation, and was only 70% of normal parenchyma volume. After 18 weeks lactation the activities of three key milk synthetic enzymes werevery similar to values previously found in natural lactations, and secretion efficiency (milk production per unit volume of parenchyma) was


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also similar to that of natural lactations. We conclude that the lower than normal milk yields were associated with incomplete proliferation ofmammary 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 Cancer5(3): 184-98.

Sophisticated genetic technologies have led to the development of mouse models of human cancers that recapitulate important features ofhuman oncogenesis. Many of these genetically engineered mouse models promise to be very relevant and relatively rapid systems fordetermining the efficacy of chemopreventive agents and their mechanisms of action. The validation of such models for chemopreventionwill 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 onprolactin 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 days18 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 had305-day lactations. Yields of milk in cows injected for 21 days were greater on day 1 and increased more rapidly until peak was reached at10 wk; daily mean production throughout lactation was greater (14.3 versus 10.1 kg) than for cows injected for 7 days. Lactation curvespooled within cow within treatment differed. Concentrations of estradiol, estrone and progesterone increased during steroid injections andwere 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 notdiffer during this time. The quantity of prolactin released in response to injection of thyrotropin releasing hormone was greater 10 days aftersteroid injections than before or during steroid injections. Preinjection concentrations of prolactin were correlated with magnitude ofpostinjection response to thyrotropin releasing hormone, but response was not correlated with concentrations of steroids in plasma on day ofinjection.

Hennighausen, L. G. and A. E. Sippel (1982). "Mouse whey acidic protein is a novel member of the family of 'four-disulfide core' proteins." NucleicAcids 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 amolecular weight of 14.0 kDa. We have deduced the amino acid sequence of this mouse acidic of whey protein from the nucleotide sequence


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of cloned cDNA. The positions of the half cysteines suggest that mouse whey acidic protein (WAP) is a two domain protein, very similar instructure to the plant lectin wheat germ agglutinin and the hypothalamic carrier protein neurophysin.

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 modelto 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 Dawleyfemale 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 localrecurrence of the primary tumor. Notwithstanding, the long period of time given for tumor metastases to develop (mean time between tumorremoval and termination was 18.5 weeks), tumor spread either to lungs or regional lymph nodes could not be established. This relativelybenign behavior of the tumor was in contrast with the morphological characteristics of the tumor, which uniformly showed the features ofadenocarcinomas. The difference in biological behavior between DMBA-induced mammary tumors in rats and malignant mammary tumorsin 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 diseasessuch as cancer and cardiovascular disease. Apples are commonly consumed and are the major contributors of phytochemicals in humandiets. It was previously reported that apple extracts exhibit strong antioxidant and antiproliferative activities and that the major part of totalantioxidant activity is from the combination of phytochemicals. Phytochemicals, including phenolics and flavonoids, are suggested to be thebioactive compounds contributing to the health benefits of apples. Here it is shown that whole apple extracts prevent mammary cancer in arat model in a dose-dependent manner at doses comparable to human consumption of one, three, and six apples a day. This studydemonstrated that whole apple extracts effectively inhibited mammary cancer growth in the rat model; thus, consumption of apples may bean 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.


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Spontaneous tumors in dogs and cats are appropriate and valid model tumor systems available for testing cancer therapeutic agents orstudying cancer biology. The pet population is a vastly underutilized resource of animals available for study. Dogs and cats developspontaneous tumors with histopathologic and biologic behavior similar to tumors that occur in humans. The tumors with potential relevancefor human cancer biology include osteosarcoma, mammary carcinoma, oral melanoma, oral squamous cell carcinoma, nasal tumors, lungcarcinoma, 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 makethis tumor particularly attractive for studying anti-metastasis approaches. Canine and feline malignant mammary tumors are fairly commonin 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 tochemotherapy and radiation has been disappointing. This tumor can be treated with anti-metastatic approaches or biological responsemodifiers. Squamous cell carcinomas, especially in the gum, are excellent models for radiation therapy studies. Nasal carcinomas arecommonly treated with radiation therapy. They tend to metastasize slowly, but have a high local recurrence rate. This tumor is suitable forstudying radiation therapy approaches. Primary lung tumors and soft tissue sarcomas are excellent models for studying combined modalitytherapy such as surgery with chemotherapy or biological response modifiers. Finally, non-Hodgkin's lymphoma is a common neoplasticprocess 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 amodel 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 epithelialcells." 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 hormonesinvolved 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 Neudifferentiation 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 tyrosinephosphorylation of erbB-2 and erbB-3. Both NDF and EGF stimulate HC11 cell proliferation and promote the responsiveness of HC11 cellsto lactogenic hormones. NDF induces the expression of a 22-kilodalton milk protein. This protein is up-regulated by other factors, includingdexamethasone, EGF, and basic fibroblast growth factor, and is controlled in a manner distinct from that of beta-casein. Like EGF, NDFinhibits the DIP-induced expression of beta-casein at the level of transcription. The inhibition is due to the negative effect of NDF on the


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activation of mammary gland factor (MGF/Stat5), a member of the Stat family of transcription factors, which is essential for beta-caseingene 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 ofbeta-casein expression." Cell Growth Differ5(3): 239-47.

Treatment of HC11 mouse mammary epithelial cells with the lactogenic hormones dexamethasone, insulin, and prolactin (DIP) leads tocellular differentiation and production of the milk protein beta-casein. The following experimental evidence suggests the involvement ofprotein kinase C (PKC) in DIP induced signal transduction. Down-regulation of PKC by 12-O-tetradecanoylphorbol-13-acetate or additionof CGP 41251, a selective inhibitor of PKC, inhibited beta-casein protein expression induced by DIP in HC11 cells. This inhibition occurs atthe level of transcription, since the DIP mediated activation of a beta-casein promoter-luciferase reporter construct or of mammary glandspecific factor (MGF), an essential transcription factor for beta-casein promoter activity, was also inhibited by CGP 41251. Inhibition ordown-regulation of PKC reduced the activation of MGF by prolactin as well. PKC-alpha, the only conventional PKC isoform expressed inHC11 cells, is most likely involved in the DIP induced beta-casein expression. (a) Only PKC-alpha and PKC-epsilon are down-regulated by12-O-tetradecanoylphorbol-13-acetate whereas PKC-delta and PKC-zeta are not. (b) Of the PKC isoforms expressed in HC11 cells, CGP41251 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, onlyPKC-alpha translocated to membrane fractions after DIP or prolactin treatment. Taken together, these data indicate that PKC-alpha plays animportant role in the signaling pathway activated by prolactin during beta-casein induction.

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 tumorvirus via a hormone response element in the viral long terminal repeat (LTR) promoter region. This report describes the investigation of thehormone responsiveness of bovine leukemia virus (BLV), an oncogenic retrovirus that infects dairy and beef cattle worldwide. It is amember of the human T cell leukemia (HTLV)/BLV group of retroviruses, which encode a protein, Tax, that is essential for regulatingtranscription of their own proviruses and for transforming host cells. We investigated the responsiveness of BLV to the hormones 17 beta-estradiol, progesterone, prolactin, insulin, and dexamethasone, a potent glucocorticoid. Only dexamethasone, in combination with insulin orinsulin/prolactin, consistently stimulated BLV expression, as measured by reverse transcriptase activity, RNA blot hybridization (Northernblots), and CAT (chloramphenicol acetyltransferase) reporter assays of cell lines transiently or stably transfected with the BLV LTR. Thiseffect required the presence of glucocorticoid receptors and Tax. This is the first report of hormone responsiveness in a virus of theHTLV/BLV group.


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Peace, B. E., K. Toney-Earley, et al. (2005). "Ron receptor signaling augments mammary tumor formation and metastasis in a murine model ofbreast 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 isthe 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+/+) andpMT+/- TK-/- mice developed mammary tumors and lung metastases. However, a significant decrease in mammary tumor initiation andgrowth was found in the pMT+/- TK-/- mice compared with controls. An examination of mammary tumors showed that there was asignificant decrease in microvessel density, significantly decreased cellular proliferation, and a significant increase in terminaldeoxynucleotidyl transferase-mediated nick end labeling-positive staining in mammary tumor cells from the pMT+/- TK-/- mice comparedwith the pMT+/- TK+/+ mice. Biochemical analyses on mammary tumor lysates showed that whereas both the pMT-expressing TK+/+ andTK-/- tumors have increased Ron expression compared with normal mammary glands, the pMT-expressing TK-/- tumors have deficits inmitogen-activated protein kinase and AKT activation. These results indicate that Ron signaling synergizes with pMT signaling to inducemammary tumor formation, growth, and metastasis. This effect may be mediated in part through the regulation of angiogenesis and throughproliferative 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 HospAssoc 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 caseof feline mammary carcinoma with skeletal metastasis to a distal limb is presented. The pertinent literature on feline mammary carcinomaand 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 beresponsible for lameness in elderly cats. Further investigation of the comparative aspects of bone metastases in cats and other species mayelucidate 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 ofapoptosis 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


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molecular mechanisms of GR-mediated survival remain poorly understood. In this study, a large-scale oligonucleotide screen of GR-regulated genes was performed. Several of the genes that were found to be induced 30 min after GR activation encode proteins that functionin cell survival signaling pathways. We also demonstrate that dexamethasone pretreatment of breast cancer cell lines inhibits chemotherapy-induced apoptosis in a GR-dependent manner and is associated with the transcriptional induction of at least two genes identified in ourscreen, 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 ofGC treatment, ectopic expression of SGK-1 or MKP-1 inhibits chemotherapy-induced apoptosis, suggesting a possible role for these proteinsin GR-mediated survival. Moreover, specific inhibition of SGK-1 or MKP-1 induction by the introduction of SGK-1- or MKP-1-smallinterfering RNA reversed the anti-apoptotic effects of GC treatment. Taken together, these data suggest that GR activation in breast cancercells regulates survival signaling through direct transactivation of genes that encode proteins that decrease susceptibility to apoptosis. Giventhe widespread clinical administration of dexamethasone before chemotherapy, understanding GR-induced survival mechanisms is essentialfor achieving optimal therapeutic responses.

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Milchbildende Hormone und Brustkrebs von Elisabeth Rieping

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