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Sergio A Arispe, Betty Adams and Thomas E Adams

Plant-derived estrogens (phytoestrogens, PEs), like endogenous estrogens, affect a diverse array of tissues, including the bone, uterus, mammary gland, and components of the neural and cardiovascular systems. We hypothesized that PEs act directly at pituitary loci to attenuate basal FSH secretion and increase gonadotrope sensitivity to GnRH. To examine the effect of PEs on basal secretion and total production of FSH, ovine pituitary cells were incubated with PEs for 48 h. Conditioned media and cell extract were collected and assayed for FSH. Estradiol (E2) and some PEs significantly decreased basal secretion of FSH. The most potent PEs in this regard were coumestrol (CM), zearalenone (ZR), and genistein (GN). The specificity of PE-induced suppression of basal FSH was indicated by the absence of suppression in cells coincubated with PEs and an estrogen receptor (ER) blocker (ICI 182 780; ICI). Secretion of LH during stimulation by a GnRH agonist (GnRH-A) was used as a measure of gonadotrope responsiveness. Incubation of cells for 12 h with E2, CM, ZR, GN, or daidzein (DZ) enhanced the magnitude and sensitivity of LH secretion during subsequent exposure to graded levels of a GnRH-A. The E2- and PE-dependent augmentation of gonadotrope responsiveness was nearly fully blocked during coincubation with ICI. Collectively, these data demonstrate that selected PEs (CM, ZR, and GN), like E2, decrease basal secretion of FSH, reduce total FSH production, and enhance GnRH-A-induced LH secretion in a manner that is dependent on the ER.

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Specific binding of radio-iodinated ovine prolactin to subcellular tissue fractions of the tammar wallaby (Macropus eugenii) was investigated. Specific binding was found, in order of decreasing binding activity, in the lactating mammary gland, corpus luteum, corpus albicans, adrenal gland and ovary. Specific binding was absent in kidney, liver, brain and inactive mammary gland.

The mean association constant (Ka at 23 °C) was determined as 0·90 × 109, 2·20 × 109, 2·44 × 109, 3·38 × 109 and 10·98 × 1091/mol for mammary gland, adrenal, corpus albicans, corpus luteum and ovary respectively. The mean receptor concentration (N) varied from 92·87 × 10−14 mol/mg protein for the mammary gland to 1·03 × 10−14 mol/mg protein for the ovary. The concentration in the corpus luteum varied between tissue pools collected at different times of the annual breeding cycle.

The specificity for prolactin was shown in the mammary gland and corpus luteum by the failure of ovine FSH, LH, GH and TSH to displace 125I-labelled ovine prolactin, whereas it was displaced readily by both ovine and bovine prolactin.

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The lactogenic properties of extracts of the pituitary glands of salmon and trout were evaluated by using the organ culture technique with rabbit mammary explants. Crude extracts and fractions obtained after chromatography on Ultrogel and selected for their capacity to compete with ovine prolactin in a rabbit mammary gland radioreceptor assay were added to the culture medium. The criteria of lactogenesis were lactose synthetase activity, casein synthesis, measurements of the concentration of casein messenger RNA and the histology of mammary glands. All these tests led to the conclusion that salmon and trout pituitary glands contain a prolactin-like principle capable of initiating milk synthesis in the rabbit mammary cell.

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VK Pedchenko and W Imagawa

Proliferation and differentiation of mammary epithelia are regulated by the combined action of systemic hormones and locally derived paracrine growth factors. Keratinocyte growth factor (KGF) is a potential candidate stromal factor that may participate in the hormonal control of stromal/epithelial interactions. In this study, we have examined the in vivo effect of 17beta-estradiol (E) treatment on KGF expression in mammary glands of peripubertal (5-week-old) and mature (11-week-old) mice. Mice received subcutaneous injections of hormone after which KGF mRNA levels were assayed by ribonuclease protection analysis of mammary gland RNA. E treatment caused a dose- and time-dependent increase in KGF mRNA levels in intact mice from both age groups. Neither 17alpha-estradiol nor progesterone injection affected KGF mRNA levels. Comparison of the relative expression of KGF in parenchyma-free fat pads and in intact glands demonstrated that the basal and E-dependent KGF mRNA levels did not require the presence of mammary epithelium. ELISA assay of KGF tissue content demonstrated that concomitantly with an up-regulation of mRNA, E treatment also increased KGF protein in mammary glands from peripubertal and mature mice. These data show that E treatment stimulates both KGF mRNA and protein expression in mammary stroma in vivo and raises the possibility that KGF has a role in E-regulated mammary gland development.

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Mammotrophic (i.e. mammogenic and/or lactogenic) activity of mouse placentae of different stages (4–19 days of pregnancy) was examined using organ co-culture of placental explants with mammary tissue. The test mammary tissues were taken from midpregnant (11–12 days) nulliparous A/Crgl mice and cultured in a synthetic medium (Waymouth's) supplemented with insulin (5 μg/ml) and aldosterone (1 μg/ml). The responses of mammary gland to placental explants were judged histologically, and were compared with those seen after the addition of ovine prolactin (5 μg/ml). With placentae from 6- to 19-day pregnant animals, distinct mammotrophic activity was seen, with the appearance of eosinophilic secretion in the mammary alveolar lumina, whereas with 4- or 5-day-old 'placentae', no mammotrophic activity was detected. Inasmuch as growth hormone does not substitute for prolactin in mammary gland development and function in the A/Crgl mouse, it can be concluded that a prolactin-like factor is present in the mouse placenta. The influence of placentae on mammary gland was further analysed by transplantation of placental fragments to mammary fat pads. Local lobuloalveolar development was prominent in some instances in the area around the placental transplants.

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Y Feuermann, S J Mabjeesh, L Niv-Spector, D Levin and A Shamay

One of the roles of the endocrine system is to synchronize mammary function. Hormones, such as estrogen, progesterone, and prolactin act directly on the mammary gland. Metabolic hormones, such as GH, glucocorticoids, insulin, and leptin are responsible for coordinating the body’s response to metabolic homeostasis. Leptin has been shown to be an important factor in regulating the metabolic adaptation of nutrient partitioning during the energy-consuming processes of lactation. In the present study, we show that leptin is secreted from the mammary fat, and is regulated by prolactin. The expression of α-casein in a co-culture of epithelial cells and fat explants was enhanced by prolactin compared with that in epithelial cells cultured alone. Leptin antagonist abolished the effect of leptin on α-casein expression in mammary gland explants when exogenous leptin was not present in the medium. This finding supports our hypothesis that the antagonist abolishes the action of endogenous leptin secreted by the mammary adipocytes. These results lead us to the hypothesis that prolactin and leptin act in the bovine mammary gland, via mammary fat pad/adipocytes.

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V K Turan, R I Sanchez, J J Li, S A Li, K R Reuhl, P E Thomas, A H Conney, M A Gallo, F C Kauffman and S Mesia-Vela

Several investigators have suggested that certain hydroxylated metabolites of 17β-estradiol (E2) are the proximate carcinogens that induce mammary carcinomas in estrogen-sensitive rodent models. The studies reported here were designed to examine the carcinogenic potential of different levels of E2 and the effects of genotoxic metabolites of E2 in an in vivo model sensitive to E2-induced mammary cancer. The potential induction of mammary tumors was determined in female ACI rats subcutaneously implanted with cholesterol pellets containing E2 (1, 2, or 3 mg), or 2-hydroxyestradiol (2-OH E2), 4-hydroxyestradiol (4-OH E2), 16α-hydroxyestradiol (16α-OH E2), or 4-hydoxyestrone (4-OH E1) (equimolar to 2 mg E2). Treatment with 1, 2, or 3 mg E2 resulted in the first appearance of a mammary tumor between 12 and 17 weeks, and a 50% incidence of mammary tumors was observed at 36, 19, and 18 weeks respectively. The final cumulative mammary tumor incidence in rats treated with 1, 2, or 3 mg E2 for 36 weeks was 50%, 73%, and 100% respectively. Treatment of rats with pellets containing 2-OH E2, 4-OH E2, 16α-OH E2, or 4-OH E1 did not induce any detectable mammary tumors. The serum levels of E2 in rats treated with a 1 or 3 mg E2 pellet for 12 weeks was increased 2- to 6-fold above control values (~30 pg/ml). Treatment of rats with E2 enhanced the hepatic microsomal metabolism of E2 to E1, but did not influence the 2- or 4-hydroxylation of E2. In summary, we observed a dose-dependent induction of mammary tumors in female ACI rats treated continuously with E2; however, under these conditions 2-OH E2, 4-OH E2, 16α-OH E2, and 4-OH E1 were inactive in inducing mammary tumors.

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C. M. Riggs, R. C. Sutherland and J. B. Wakerley


Experiments were performed to reinvestigate the importance of mammary engorgement for activation of the milk-ejection reflex in the rat. Reflex milk ejection (measured by intramammary pressure recordings during a 2-h suckling test under anaesthesia) was compared in rats with engorged mammary glands (15-h separation from the pups, followed by sham-removal of milk) and in rats with drained mammary glands (15-h separation, followed by milk removal using a foster litter and exogenous oxytocin).

In experiment 1, multiple small (2 mu.) doses of oxytocin were used for milk removal: these were effective in emptying the mammary glands and caused no subsequent impairment or change in sensitivity of the mammary response to oxytocin. Using this draining procedure, no significant differences were observed in either the number or relative amplitude of the milk ejections, or the occurrence of pup stretch reactions between engorged and drained rats. Similar results were seen in experiment 2, where an identical draining protocol was used, but the rats were pretreated with propranolol before the suckling test. In experiment 3, large (250 mu.) oxytocin doses were used for milk removal, as in previous studies. Again mammary draining had no effect on milk ejection in a subsequent suckling test (with propranolol pretreatment). However, the number of stretch reactions shown by the pups was significantly (P < 0·001) reduced from 8·6 ± 1·4/2 h to 1·9 ± 0·6/2 h. This effect probably related to long-term impairment of the oxytocin response of the mammary glands following the draining procedure, and could not be attributed to the draining per se. The dissociation of milk ejections and pup behavioural responses using this method of draining the glands explains previous reports, based on behavioural observations, that mammary draining profoundly disrupts milk ejection. It is concluded that mammary engorgement in fact has little influence on the activation of the milk-ejection reflex in the rat.

J. Endocr. (1985) 105, 127–132

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Darryl L Hadsell, Walter Olea, Nicole Lawrence, Jessy George, Daniel Torres, Takahashi Kadowaki and Adrian V Lee

Expression of insulin receptor substrates (IRS)-1 and -2 within the mammary gland was found to be high at mid-lactation and dramatically decreased with mammary involution. This observation supports the hypothesis that these proteins are induced in the mammary gland with lactogenesis and involved in normal milk synthesis. To test this hypothesis, lactation capacity, along with indices of mammary secretory cell glucose metabolism and cell signaling were compared in normal mice and mice carrying targeted mutations in either the Irs1 or Irs2 genes. Mammary IRS-1 and IRS-2 protein levels were increased within 1 day of parturition and reached maximal levels by 5 days post partum. Dams carrying germline mutations of Irs1 or Irs2 displayed reduced lactation capacity as assessed by weight gain of pup litters. The reduction was more dramatic in Irs1 −/− versus Irs2 −/− dams. Maternal body weight was also reduced in Irs1 −/− dams as well as in Irs1 +/− Irs2 +/− dams. The loss of IRS-1 had little impact on mammary gland expression of milk protein mRNAs, glucose transport, or on the abundance and subcellular localization of hexokinases I and II. The loss of IRS-1 was associated with a compensatory increase in insulin-induced IRS-2 phosphorylation; however, the loss of IRS-1 did also cause a reduction in insulin-dependent mammary gland-specific activation of Akt phosphorylation. These results support the conclusion that IRS-1 is important for insulin-dependent activation of Akt signaling within the lactating mammary gland, but that loss of this protein has only modest impact on normal milk synthesis, since related signaling proteins such as IRS-2 may act in compensatory fashion.

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Maria Theresa E Montales, Omar M Rahal, Hajime Nakatani, Tsukasa Matsuda and Rosalia C M Simmen

Mammary adipose tissue may contribute to breast cancer development and progression by altering neighboring epithelial cell behavior and phenotype through paracrine signaling. Dietary exposure to soy foods is associated with lower mammary tumor risk and reduced body weight and adiposity in humans and in rodent breast cancer models. Despite the suggested linkage between obesity and breast cancer, the local influence of bioactive dietary components on mammary adiposity for antitumor effects remains unknown. Herein, we report that post-weaning dietary exposure to soy protein isolate and its bioactive isoflavone genistein (GEN) lowered mammary adiposity and increased mammary tumor suppressor PTEN and E-cadherin expression in female mice, relative to control casein diet. To ascertain GEN's role in mammary adipose deposition that may affect underlying epithelial cell phenotype, we evaluated GEN's effects on SV40-immortalized mouse mammary stromal fibroblast-like (MSF) cells during differentiation into adipocytes. MSF cells cultured in a differentiation medium with 40 nM GEN showed reductions in mature adipocyte numbers, triglyceride accumulation, and Ppar γ (Pparg) and fatty acid synthase transcript levels. GEN inhibition of adipose differentiation was accompanied by increased estrogen receptor β (Er β (Esr2)) gene expression and was modestly recapitulated by ERβ-selective agonist 2,3-bis-(4-hydroxyphenyl)-propionitrile (DPN). Reduction of Er β expression by siRNA targeting increased Ppar γ transcript levels and stromal fibroblast differentiation into mature adipocytes; the latter was reversed by GEN but not by DPN. Conditioned medium from GEN-treated adipocytes diminished anchorage-independent mammosphere formation of human MCF-7 breast cancer cells. Our results suggest a mechanistic pathway to support direct regulation of mammary adiposity by GEN for breast cancer prevention.