scholarly journals Local over-expression of prolactin in differentiating mouse mammary gland induces functional defects and benign lesions, but no carcinoma

2006 ◽  
Vol 190 (2) ◽  
pp. 271-285 ◽  
Author(s):  
Caroline Manhès ◽  
Christine Kayser ◽  
Philippe Bertheau ◽  
Bruce Kelder ◽  
John J Kopchick ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Epidemiological Data ◽  
Mammary Glands ◽  
Mouse Mammary Gland ◽  
Late Gestation ◽  
Benign Tumors ◽  
Milk Whey ◽  
Over Expression ◽  
Morphological Defects ◽  
Lymphocytic Infiltrates

Experimental, clinical, and epidemiological data support the growth-promoting role of endocrine prolactin (PRL) in mammary tumors. PRL is also produced by the breast, where it is now recognized to act as a growth/survival factor via autocrine/paracrine mechanisms. Recent transgenic (Tg) mouse models have revealed the pro-oncogenic effect of PRL over-expression in virgin mammary glands. To address the question whether PRL tumorigenicity was maintained on differentiated mammary glands, we generated mammary-specific Tg mice expressing human (h)PRL under the control of the milk whey acidic protein promoter, which directs autocrine hPRL over-expression in late gestation throughout lactation. Minimal levels of transgene expression were detected in the mammary glands of virgin animals, which at best induced partial ductal branching and lobulo-alveolar structures in older nulliparous females. As expected, expression of mammary hPRL dramatically increased at the end of first pregnancy, and from this point it never returned to baseline, although it peaked at each gestation/lactation cycle. Over-expression of hPRL that starts when the gland is already well into the differentiation process led to various morphological mammary alterations, including abnormally differentiated epithelium, atropy of the myoepithelial layer, dilated ducts, cysts, and lymphocytic infiltrates. These phenotypes tended to worsen with successive pregnancies, also reflecting cumulative damage of failure of involution. Although some older, multiparous females developed benign tumors (papillomas and metaplasias), none of the animals studied developed mammary carcinomas. In addition, we noticed that half of the Tg females exhibited lactation defects, leading to significantly increased pup mortality. This phenotype was due neither to failure of milk production nor to modification of its protein content, but rather it was correlated to lipid enrichment of the milk, which, in combination with profoundly altered morphology of the gland, led to impaired milk extrusion through the nipple. In summary, these data show that over-expression of autocrine hPRL in a differentiating mammary gland induces dramatic functional and morphological defects, but not carcinoma. This deserves further investigations on the emerging concept that autocrine PRL may have different effects on pathological development of the mammary gland depending on the differentiation state of the latter.

scholarly journals Intraductal cystadenopapillomas of the mammary glands: diagnosis and treatment

2021 ◽  
Vol 70 (2) ◽  
Author(s):  
Diana Danilov ◽  
◽  
Veronica Svet ◽  
Ion Mereuta ◽  
◽  
...  
Keyword(s):  
Mammary Gland ◽  
Mammary Glands ◽  
Diagnosis And Treatment ◽  
Benign Tumors ◽  
Hormonal Changes ◽  
Basic Treatment

About one in two women has symptoms of breast formation. According to various data, the frequency of detection of benign pathologies of the mammary gland is much higher compared to the frequency of referring women to the doctor with these pathologies. Benign tumors of the mammary gland are characterized by a slow, expansive growth (compresses the neighboring tissue), are well encapsulated, most are the result of hormonal changes (hyperestrogenemia, hyperprolactinemia), after excision rarely recur, do not invade local tissues and do not metastasize to others. organs. The basic treatment is surgery – excision of the breast formations. Recurrences rarely occur, do not invade adjacent tissues and do not metastasize to other organs.

scholarly journals The differential actions of cortisol on the synthesis and turnover of alpha-lactalbumin and casein and on accumulation of their mRNA in mouse mammary gland in organ culture

1983 ◽  
Vol 212 (2) ◽  
pp. 507-515 ◽  
Author(s):  
Y Nagamatsu ◽  
T Oka
Keyword(s):  
Mammary Gland ◽  
Marked Decrease ◽  
Milk Proteins ◽  
Mammary Glands ◽  
Mouse Mammary Gland ◽  
Marked Enhancement ◽  
Pregnant Mice ◽  
Translatable Mrna ◽  
Casein Synthesis ◽  
Alpha Lactalbumin

Cortisol was previously shown to exert different, concentration-dependent, effects on the accumulation of casein and alpha-lactalbumin in mammary glands from mid-pregnant mice cultured in the presence of insulin and prolactin [Ono & Oka (1980) Cell 19, 473-480]. The present study demonstrated that the addition of 30nM-cortisol to the medium containing insulin and prolactin resulted in a marked enhancement of the rate of synthesis of both alpha-lactalbumin and casein in cultured tissue. The addition of 3 microM-cortisol in combination with insulin and prolactin caused a marked decrease in the rate of alpha-lactalbumin synthesis, but increased casein synthesis substantially. Similar changes were also observed in the amount of translatable mRNA for alpha-lactalbumin and casein in mammary explants cultured with insulin, prolactin and the two concentrations of cortisol. The study of the turnover of the milk proteins in cultured explants showed that virtually all of the casein synthesized remained intact in tissue explants cultured with 3 microM cortisol, whereas about 45% of casein disappeared in 40h from explants cultured with 30nM-cortisol. In contrast, the two concentrations of cortisol did not differentially affect the disappearance of alpha-lactalbumin, which was about 55% in 40h. These results indicate that the concentration-dependent differential actions of cortisol on the accumulation of alpha-lactalbumin and casein are exerted through its effects on the rate of synthesis and turnover of the two proteins as well as on the accumulation of their mRNA species.

Differential expression of the growth hormone receptor and growth hormone-binding protein in epithelia and stroma of the mouse mammary gland at various physiological stages

1999 ◽  
Vol 161 (1) ◽  
pp. 77-87 ◽  
Author(s):  
YN Ilkbahar ◽  
G Thordarson ◽  
IG Camarillo ◽  
F Talamantes
Keyword(s):  
Growth Hormone ◽  
Mammary Gland ◽  
Epithelial Cells ◽  
Growth Hormone Receptor ◽  
Mammary Epithelial Cells ◽  
Late Pregnancy ◽  
Mammary Glands ◽  
Mouse Mammary Gland ◽  
Mammary Epithelial ◽  
Mrna Levels

Increasing evidence suggests that GH is important in normal mammary gland development. To investigate this further, we studied the distribution and levels of growth hormone receptor (GHR) and GH-binding protein (GHBP) in the mouse mammary gland. At three weeks of age, the epithelial component of the right fourth inguinal mammary gland of female mice was removed. These animals were then either maintained as virgins until they were killed or they were mated. One group of the mated mice was killed on day 18 of pregnancy and the remaining mated animals were allowed to carry their pups until term and were killed on day 6 of lactation. At the time of death, both the intact left and the de-epithelialized right mammary glands were collected from all three groups. Some of the intact glands served as a source of epithelial cells, free of stroma. The mRNA levels for GHR and GHBP were measured in intact glands, epithelia-cleared fat pads, and isolated mammary epithelial cells. GHR and GHBP mRNAs were expressed in both the mammary epithelium and stroma. However, the levels of both GHR and GHBP mRNAs were significantly higher in the stroma as compared with the epithelium component. This increase for both mRNAs was from 3- to 12-fold at each physiological state examined. In the intact gland, both GHR and GHBP transcripts were highest in virgins, declined during late pregnancy, and the lowest levels were found in the lactating gland. GHBP and GHR protein concentrations were also assessed in intact glands and epithelia-free fat pads. Similar to the mRNAs, GHR and GHBP protein levels (means+/-s.e.m.) in intact glands were highest in virgin mice (0.891+/-0.15 pmoles/mg protein and 0.136+/-0.26 pmoles/mg protein respectively), declined during late pregnancy (0. 354+/-0.111 pmoles/mg protein and 0.178+/-0.039 pmoles/mg protein respectively), and were lowest during lactation (0.096+0.037 pmoles/mg protein and 0.017+0.006 pmoles/mg protein respectively). Immunocytochemistry utilizing specific antisera against mouse (m) GHR and mGHBP revealed that the two proteins are localized to both the stroma and parenchyma of mouse mammary glands, with similar patterns of immunostaining throughout the different physiological stages analyzed. GHR immunolocalized to the plasma membrane and cytosol of mammary epithelial cells and adipocytes, whereas the GHBP immunostaining was nuclear and cytosolic. In conclusion, we report here that GHR and GHBP mRNAs and proteins are expressed in both the epithelium and the stroma of mammary glands of virgin, pregnant, and lactating mice. In intact glands, GHR and GHBP proteins, as well as their transcripts are higher in abundance in virgin relative to lactating mice. At all physiological stages, GHR and GHBP mRNA levels are higher in the stroma compared with the parenchyma. These findings indicate that the actions of GH in the mammary gland are both direct through its binding to the epithelia, and indirect by binding to the stroma and stimulation of IGF-I production which, in turn, affects mammary epithelial development.

INTERACTION BETWEEN PROLACTIN AND THYROXINE IN MOUSE MAMMARY GLAND LOBULO-ALVEOLAR DEVELOPMENT IN VITRO

1969 ◽  
Vol 45 (4) ◽  
pp. 579-583 ◽  
Author(s):  
D. V. SINGH ◽  
H. A. BERN
Keyword(s):  
Mammary Gland ◽  
Synergistic Effects ◽  
Synthetic Medium ◽  
Mammary Glands ◽  
Mouse Mammary Gland ◽  
Intact Female ◽  
Antagonistic Effects ◽  
Alveolar Development ◽  
Development In Vitro

SUMMARY Intact female BALB/cCrgl mice, 3–4 weeks old, were pretreated with oestrogen and progesterone for 9 days. Whole mammary glands from these mice were cultivated for 5 days in a synthetic medium supplemented with aldosterone (A), prolactin (MH) and insulin (I), with and without thyroxine (T4) at concentrations ranging from 0·01 to 5 μg./ml. A medium containing 1 μg. A +5 μg.MH +5 μg.I/ml. was generally optimal for lobulo-alveolar development. Addition of thyroxine to this combination resulted in a decrease in development which was highly significant at higher concentrations. However, when cultures were maintained in media containing suboptimal or low amounts of prolactin (1 μg. A + 3 μg. MH +5 μg. I/ml. and 1 μg. A + 1 μg. MH +5 μg. I/ml., respectively), the results indicate two possible effects of thyroxine: lower amounts of thyroxine had synergistic effects, whereas greater amounts had antagonistic effects on lobulo-alveolar development.

scholarly journals Altered mammary epithelial development, pattern formation and involution in transgenic mice expressing the EphB4 receptor tyrosine kinase

2002 ◽  
Vol 115 (1) ◽  
pp. 25-37
Author(s):  
Nadia Munarini ◽  
Richard Jäger ◽  
Susanne Abderhalden ◽  
Gisela Zuercher ◽  
Valeria Rohrbach ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Transgenic Mice ◽  
Apoptotic Cell ◽  
Mammary Epithelium ◽  
Transgenic Animals ◽  
Mammary Glands ◽  
Mouse Mammary Gland ◽  
Mammary Epithelial ◽  
Cellular Growth ◽  
Mmtv Ltr

We have previously documented the cell-type-specific and hormone-dependent expression of the EphB4 receptor in the mouse mammary gland. To investigate its role in the biology of the mammary gland, we have established transgenic mice bearing the EphB4 receptor under the control of the MMTV-LTR promoter, which represents the first transgenic mouse model to investigate the effect(s) of unscheduled expression of EphB4 in adult organisms. Transgene expression in the mammary epithelium was induced at puberty, increased during pregnancy, culminated at early lactation and persisted until day three of post-lactational involution. In contrast, expression of the endogenous EphB4 gene is downregulated during pregnancy, is essentially absent during lactation and is re-induced after day three of post-lactational involution. The unscheduled expression of EphB4 led to a delayed development of the mammary epithelium at puberty and during pregnancy. During pregnancy, less lobules were formed, these however exhibited more numerous but smaller alveolar units. Transgenic mammary glands were characterized by a fragile, irregular morphology at lactation; however, sufficient functionality was maintained to nourish the young. Transgenic mammary glands exhibited untimely epithelial apoptotic cell death during pregnancy and abnormal epithelial DNA synthesis at early post-lactational involution, indicating a disturbed response to proliferative/apoptotic signals. Mammary tumours were not observed in the EphB4 transgenic animals; however, in double transgenic animals expressing both EphB4 and the neuT genes, tumour appearance was significantly accelerated and, in contrast to neuT-only animals, metastases were observed in the lung. These results implicate EphB4 in the regulation of tissue architecture, cellular growth response and establishment of the invasive phenotype in the adult mammary gland.

scholarly journals Local Insulin-Like Growth Factor-II Mediates Prolactin-Induced Mammary Gland Development

2003 ◽  
Vol 17 (3) ◽  
pp. 460-471 ◽  
Author(s):  
Russell C. Hovey ◽  
Jessica Harris ◽  
Darryl L. Hadsell ◽  
Adrian V. Lee ◽  
Christopher J. Ormandy ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Early Pregnancy ◽  
Insulin Receptors ◽  
Mammary Glands ◽  
Mouse Mammary Gland ◽  
Mammary Epithelial ◽  
Receptor Expression ◽  
Mammary Tissue ◽  
Alveolar Development

Abstract Prolactin (PRL) is a major determinant of mammary epithelial cell proliferation during alveolar development in sexually mature and pregnant mice. To date, it has not been clear whether PRL effects these responses alone or by also invoking the action of autocrine/paracrine growth factors. In this study, we provide evidence that part of the effect of PRL on mammary gland growth is mediated by IGF-II. During sexual maturity and in early pregnancy, the level of IGF-II mRNA in the mammary gland was increased concurrent with increased PRL receptor expression. The level of IGF-II mRNA was reduced in mammary tissue from PRL receptor−/− mice during early pregnancy, and explants of mouse mammary gland and HC11 mammary epithelial cells both increased their expression of IGF-II after exposure to PRL in vitro. These findings coincided with the demonstration that IGF-II stimulated alveolar development in mammary glands in whole organ culture. PRL was most efficacious in stimulating IGF-II gene transcription from promoter 3 of the mouse IGF-II gene in vitro. Insight into the mechanism by which PRL induced IGF-II expression was provided by the fact that it was blocked by the Jak2 inhibitor AG490 and the MAPK inhibitor PD98059. Finally, induction of insulin receptor substrate (IRS)-1 in the mammary glands of PRL-treated mice and induction of IRS-1 and IRS-2 after treatment with PRL plus progesterone indicates that these molecules are induced by PRL as potential signaling intermediates downstream from IGF-I/insulin receptors. Together, these data demonstrate a role for IGF-II as a mediator of PRL action in the mouse mammary gland during ductal branching and alveolar development.

scholarly journals Exposure to the Endocrine Disruptor, Propylparaben, During Pregnancy and Lactation, Alters Typical Parity-Induced Reorganization of the Mouse Mammary Gland

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A487-A488
Author(s):  
Joshua Philip Mogus
Keyword(s):  
Breast Cancer ◽  
Mammary Gland ◽  
Cancer Risk ◽  
Immune Cell ◽  
Mammary Glands ◽  
Mouse Mammary Gland ◽  
Receptor Expression ◽  
Intermediate Phenotypes ◽  
Sensitive Organ ◽  
Pregnancy And Lactation

Abstract The mammary gland is a hormone sensitive organ that is susceptible to endocrine disrupting chemicals (EDCs) during several vulnerable periods, including pregnancy and lactation. Mammary gland reorganization during pregnancy and lactation is hormone driven and provides long-term protection against breast cancer risk. It is unknown if EDC exposures during these sensitive windows can alter mammary reorganization to either enhance or offset parity-induced protection against breast cancer. Here, we examined effects of propylparaben (PP), a common preservative used in personal care products and foods with estrogen receptor (ER) agonist properties, on the parous mouse mammary gland. Pregnant BALB/c mice were treated with 0, 20, 100, or 10,000 µg/kg/day PP throughout pregnancy and lactation. These doses were selected for their relevance to human exposures. We also included an unexposed nulliparous female group to evaluate the typical changes associated with parity. Five weeks post-involution (and five weeks after the last PP exposure), mammary glands were collected and assessed for changes in histomorphology, hormone receptor expression, immune cell number, and gene expression. We found that PP reduced many of the typical morphological effects of parity on the mammary gland, resulting in intermediate phenotypes for ductal density and total epithelial structures. Notably, we found increased proliferation in PP-treated mammary glands, despite decreased ductal epithelial volume relative to parous controls. Mammary glands from PP-treated females also had alterations in the expression of ERα-mediated genes, including PgR (the gene that encodes progesterone receptor) and Igf1, with expression levels that were intermediate to both nulliparous and parous control mice. Finally, PP reduced the effect of parity on several immune cell types in the mammary gland including B cells, T-cells, and M2 macrophages. These results suggest that PP, at levels relevant to human exposure, can disrupt the normal response to parity in the mouse mammary gland, including persistent alterations to mammary gland structures. Future studies should address whether PP exposures disturb the protective effects of pregnancy on mammary cancer risk.

Mammary gland development of sows injected with growth hormone-releasing factor during gestation and(or) lactation

1997 ◽  
Vol 77 (2) ◽  
pp. 335-338 ◽  
Author(s):  
C. Farmer ◽  
G. Pelletier ◽  
P. Brazeau ◽  
D. Petitclerc
Keyword(s):  
Growth Hormone ◽  
Mammary Gland ◽  
Key Words ◽  
Mammary Gland Development ◽  
Mammary Glands ◽  
Late Gestation ◽  
Chemical Analyses ◽  
Growth Hormone Releasing Factor ◽  
Mammary Cell ◽  
Gland Development

Twenty-four gilts received s.c. injections of saline or growth hormone-releasing factor (GRF) in late gestation and(or) lactation. Sows were sacrificed on day 30 of lactation and functional mammary glands were excised for chemical analyses. Weight of parenchymal (P = 0.004) and extra-parenchymal tissues (P = 0.002) were decreased with GRF injections during lactation. Parenchymal mass per milligram of DNA also decreased (P = 0.025) with GRF in lactation while parenchymal DNA concentration increased (P = 0.03). Exogenous GRF given to sows during lactation therefore decreased total parenchymal mass, increased cell density and decreased mammary cell size. Key words: Sow, mammary gland, growth hormone-releasing factor

Lactational competence and involution of the mouse mammary gland require plasminogen

Development ◽  
2000 ◽  
Vol 127 (20) ◽  
pp. 4481-4492 ◽  
Author(s):  
L.R. Lund ◽  
S.F. Bjorn ◽  
M.D. Sternlicht ◽  
B.S. Nielsen ◽  
H. Solberg ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Matrix Metalloproteinases ◽  
Plasminogen Activator ◽  
Mammary Gland Development ◽  
Mammary Glands ◽  
Mouse Mammary Gland ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Gland Development ◽  
Dose Dependent

Urokinase-type plasminogen activator expression is induced in the mouse mammary gland during development and post-lactational involution. We now show that primiparous plasminogen-deficient (Plg(−/−)) mice have seriously compromised mammary gland development and involution. All mammary glands were underdeveloped and one-quarter of the mice failed to lactate. Although the glands from lactating Plg(−/−) mice were initially smaller, they failed to involute after weaning, and in most cases they failed to support a second litter. Alveolar regression was markedly reduced and a fibrotic stroma accumulated in Plg(−/−) mice. Nevertheless, urokinase and matrix metalloproteinases (MMPs) were upregulated normally in involuting glands of Plg(−/−) mice, and fibrin did not accumulate in the glands. Heterozygous Plg(+/−) mice exhibited haploinsufficiency, with a definite, but less severe mammary phenotype. These data demonstrate a critical, dose-dependent requirement for Plg in lactational differentiation and mammary gland remodeling during involution.

In vitro analysis of the hormonal basis for the sexual dimorphism in the embryonic development of the mouse mammary gland

Development ◽  
1971 ◽  
Vol 25 (1) ◽  
pp. 141-153
Author(s):  
Klaus Kratochwil
Keyword(s):  
Mammary Gland ◽  
Sexual Dimorphism ◽  
Embryonic Development ◽  
Mammary Glands ◽  
Mouse Mammary Gland ◽  
Female Type ◽  
Male Type ◽  
Endocrine Organs ◽  
Vitro Analysis

Factors underlying the sexual dimorphism in the embryonic development of mouse mammary glands were analysed in vitro and the following results were obtained: 1. Mammary gland rudiments of 13-day male embryos, explanted immediately before the onset of their regression, were perfectly capable of developing into female-type glands in vitro. Even some of the glands of 14-day male embryos, where the regression process had already begun, recovered after explantation and underwent female-type morphogenesis. 2. Combined explantation of 13-day testes with mammary rudiments of female embryos of 12–14 days gestation resulted in male-type regression of the glands. 3. The addition of testosterone to the culture medium caused a similar regression of explanted (female) mammary-gland rudiments. The minimal effective concentration of the hormone was 10−9m, or 0·00029 μg/ml. 4. Cultured mammary rudiments of 15-day female embryos were no longer responsive to the presence of testis explants. They failed to undergo regression and continued their development in vitro. From these results the following conclusions were drawn: (a) The sexual dimorphism in the embryonic development of mouse mammary glands is caused by their suppression in males and not by their stimulation in female embryos. (b) The androgenic hormones in male foetuses are solely responsible for the regression of the mammary rudiments. They exert their effect directly on the gland without the need for involvement of other endocrine organs. (c) The genetic sex of the gland itself has no influence on its developmental capacities as: (i) glands of male embryos are able to develop in the absence of androgens, and (ii) glands of female embryos undergo typical male-type regression in vitro when exposed to the presence of foetal testes or of testosterone.

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