THE INFLUENCE OF RELAXIN ON MAMMARY GLAND DEVELOPMENT IN GUINEA-PIGS AND RABBITS

An attempt has been made to determine the influence of relaxin on the early development of the mammary glands in rabbits and guinea-pigs. Spayed females of both species were treated with α-oestradiol and an extract containing relaxin, after a preliminary course of the steroid alone. In all cases the total treatment was limited to 20 days. Animals given only oestradiol served as controls. While the data presented are insufficient to substantiate without doubt an influence of relaxin per se on the development of the mammary tissue, they indicate that it enhances mammary development. In the guinea-pig this was in the form of a general growth stimulus; in the rabbit it appeared to consist of a transfer of emphasis from primary duct development to that of the entire duct system of the gland. The conclusion drawn from this study is that relaxin acts as a potentiator of oestrogen, working with the latter to produce greater and more normal development of the mammary glands.

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Expression levels of STAT5A and STAT5B in mammary parenchymal tissue from Upton-Meishan and Large White gilts

Canadian Journal of Animal Science ◽

10.4141/a01-091 ◽

2002 ◽

Vol 82 (4) ◽

pp. 507-518 ◽

Cited By ~ 11

Author(s):

M. F. Palin ◽

D. Beaudry ◽

C. Roberge ◽

C. Farmer

Keyword(s):

Mammary Gland ◽

Mammary Gland Development ◽

Target Genes ◽

Mammary Glands ◽

Mammary Tissue ◽

Mrna Levels ◽

Large White ◽

Parenchymal Tissue ◽

Tissue Weight ◽

Gland Development

The implication of STAT5A and STAT5B in mammary gland development and maintenance of lactation is well documented in rodents and humans. However, little is known regarding their roles in mammary gland development during gestation in pigs. We identified and analyzed the complete coding sequences of swine STAT5A and STAT5B and evaluated their mRNA levels in mammary glands of gestating gilts (day 110) in two different breeds, Upton-Meishan and Large White. Sequence analysis revealed a new APASA insertion in the STAT5A amino acid sequence that is in close proximity to residue Tyr 699 and whose phosporylation leads to the activation of target genes’ transcription. STAT5A mRNA levels were higher in Upton-Meishan than in Large White. In both breeds, STAT5B mRNA levels were higher than those of STAT5A , which is contrary to what was found in other mammals. A correlation between circulating IGF-I levels and STAT5B mRNA levels in the mammary gland was noticed in the Upton-Meishan breed only. STAT5B mRNA levels in mammary tissue of Large White gilts were highly correlated with extra-parenchymal tissue weight, parenchymal tissue weight, total parenchymal DNA, RNA and RNA/DNA ratio. In Upton-Meishan gilts, correlations were observed only between extra-parenchymal weight and STAT5A and STAT5B mRNA levels. These results indicate that there are significant differences in mRNA levels of STAT5A and STAT5B in the mammary glands of pregnant gilts when compared to other mammals, and between swine breeds. Key words: Mammary glands, signal transducers, pregnancy, kinases, pig, expression

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A Functional Connection between pRB and Transforming Growth Factor β in Growth Inhibition and Mammary Gland Development

Molecular and Cellular Biology ◽

10.1128/mcb.00473-09 ◽

2009 ◽

Vol 29 (16) ◽

pp. 4455-4466 ◽

Cited By ~ 15

Author(s):

Sarah M. Francis ◽

Jacqueline Bergsied ◽

Christian E. Isaac ◽

Courtney H. Coschi ◽

Alison L. Martens ◽

...

Keyword(s):

Mammary Gland ◽

Growth Factor ◽

Growth Inhibition ◽

Mammary Gland Development ◽

Transforming Growth Factor ◽

Critical Role ◽

Transforming Growth Factor Β ◽

Mammary Development ◽

Functional Connection ◽

Gland Development

ABSTRACT Transforming growth factor β (TGF-β) is a crucial mediator of breast development, and loss of TGF-β-induced growth arrest is a hallmark of breast cancer. TGF-β has been shown to inhibit cyclin-dependent kinase (CDK) activity, which leads to the accumulation of hypophosphorylated pRB. However, unlike other components of TGF-β cytostatic signaling, pRB is thought to be dispensable for mammary development. Using gene-targeted mice carrying subtle missense changes in pRB (Rb1 ΔL and Rb1NF ), we have discovered that pRB plays a critical role in mammary gland development. In particular, Rb1 mutant female mice have hyperplastic mammary epithelium and defects in nursing due to insensitivity to TGF-β growth inhibition. In contrast with previous studies that highlighted the inhibition of cyclin/CDK activity by TGF-β signaling, our experiments revealed that active transcriptional repression of E2F target genes by pRB downstream of CDKs is also a key component of TGF-β cytostatic signaling. Taken together, our work demonstrates a unique functional connection between pRB and TGF-β in growth control and mammary gland development.

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Progesterone receptor membrane component 1 is required for mammary gland development†

Biology of Reproduction ◽

10.1093/biolre/ioaa164 ◽

2020 ◽

Vol 103 (6) ◽

pp. 1249-1259

Author(s):

Globinna Kim ◽

Jong Geol Lee ◽

Seung-A Cheong ◽

Jung-Min Yon ◽

Myeong Sup Lee ◽

...

Keyword(s):

Mammary Gland ◽

Progesterone Receptor ◽

Mammary Gland Development ◽

Target Genes ◽

Hormone Treatment ◽

Mammary Glands ◽

Membrane Component ◽

Independent Manner ◽

Receptor Membrane ◽

Gland Development

Abstract The physiological functions of progesterone (P4) in female reproductive organs including the mammary glands are mediated via the progesterone receptor (PR), but not all P4 functions can be explained by PR-mediated signaling. Progesterone receptor membrane component 1 (PGRMC1), a potential mediator of P4 actions, plays an important role in the ovary and uterus in maintaining female fertility and pregnancy, but its function in mammary glands has not been elucidated. This study investigated the role of PGRMC1 in mouse mammary gland development. Unlike in the uterus, exogenous estrogen (E2) and/or P4 did not alter PGRMC1 expression in the mammary gland, and Pgrmc1-knockout (KO) mice displayed reduced ductal elongation and side branching in response to hormone treatment. During pregnancy, PGRMC1 was expressed within both the luminal and basal epithelium and gradually increased with gestation and decreased rapidly after parturition. Moreover, although lactogenic capacity was normal after parturition, Pgrmc1 KO resulted in defective mammary gland development from puberty until midpregnancy, while the expression of PR and its target genes was not significantly different between wild-type and Pgrmc1-KO mammary gland. These data suggest that PGRMC1 is essential for mammary gland development during puberty and pregnancy in a PR-independent manner.

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Expression and localisation of oestrogen and progesterone receptors in the bovine mammary gland during development, function and involution

Journal of Endocrinology ◽

10.1677/joe.0.1770305 ◽

2003 ◽

Vol 177 (2) ◽

pp. 305-317 ◽

Cited By ~ 52

Author(s):

D Schams ◽

S Kohlenberg ◽

W Amselgruber ◽

B Berisha ◽

MW Pfaffl ◽

...

Keyword(s):

Mammary Gland ◽

Epithelial Cells ◽

Mrna Expression ◽

Western Blotting ◽

Mammary Gland Development ◽

Mammary Tissue ◽

Positive Staining ◽

Bovine Mammary Gland ◽

Total Rna ◽

Gland Development

It is now well established that oestrogen and progesterone are absolutely essential for mammary gland development. Lactation can be induced in non-pregnant animals by sex steroid hormone treatment. Most of the genomic actions of oestrogens are mediated by two oestrogen receptors (ER)-alpha and ERbeta, and for gestagens in ruminants by the progesterone receptor (PR). Our aim was the evaluation of mRNA expression and protein (localisation and Western blotting) during mammogenesis, lactogenesis, galactopoiesis (early, middle and late) and involution (8, 24, 28, 96-108 h and 14-28 days after the end of milking) in the bovine mammary gland (total no. 53). During these stages, the mRNA was assessed by means of real-time RT-PCR (LightCycler). The protein for ERalpha, ERbeta and PR was localised by immunohistochemistry and Western blotting. The mRNA expression results indicated the existence of ERalpha, ERbeta and PR in bovine mammary gland. Both ERalpha and PR are expressed in fg/ micro g total RNA range. The highest mRNA expression was found for ERalpha and PR in the tIssue of non-pregnant heifers, followed by a significant decrease to a lower level at the time of lactogenesis with low concentrations remaining during lactation and the first 4 weeks of involution. In contrast, the expression of ERbeta was about 1000-fold lower (ag/ micro g total RNA) and showed no clear difference during the stages examined, with a significant increase only 2-4 weeks after the end of milking. Immunolocalisation for ERalpha revealed a strong positive staining in nuclei of lactocytes in non-pregnant heifers, became undetectable during pregnancy, lactogenesis and lactation, and was again detectable 14-28 days after the end of milking. In contrast, PR was localised in the nuclei of epithelial cells in the mammary tIssue of non-pregnant heifers, in primigravid animals, and during late lactation and involution. During lactogenesis, peak and mid lactation, fewer nuclei of epithelial cells were positive, but increased staining of the cytoplasm of epithelial cells was obvious. ERalpha and ERbeta protein was found in all mammary gland stages examined by Western blotting. In contrast to mRNA expression, the protein signal for ERalpha was weaker in the tIssue of non-pregnant heifers and during involution (4 weeks). ERbeta protein showed a stronger signal (two isoform bands) in non-pregnant heifers and 4 weeks after the end of milking. This correlated with the mRNA expression data. Three isoforms of PR (A, B and C) were found by Western blotting in the tIssue of non-pregnant heifers, but only isoform B remained during the following stages (lactogenesis, galactopoiesis and involution). In conclusion, the mRNA expression and protein data for ER and PR showed clear regulatory changes, suggesting involvement of these receptors in bovine mammary gland development and involution.

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Strain-Specific Differences in the Mechanisms of Progesterone Regulation of Murine Mammary Gland Development

Endocrinology ◽

10.1210/en.2008-1459 ◽

2008 ◽

Vol 150 (3) ◽

pp. 1485-1494 ◽

Cited By ~ 45

Author(s):

Mark D. Aupperlee ◽

Alexis A. Drolet ◽

Srinivasan Durairaj ◽

Weizhong Wang ◽

Richard C. Schwartz ◽

...

Keyword(s):

Mammary Gland ◽

Mammary Gland Development ◽

Nuclear Factor Κb ◽

Mammary Development ◽

Normal Mammary Gland ◽

Human Populations ◽

Induced Expression ◽

Altered Expression ◽

Downstream Effectors ◽

Gland Development

Progesterone (P) is required for normal mammary gland development, and is implicated in the etiology of mammary cancer in rodents and humans. We analyzed mammary gland developmental responses to P and estrogen (E) in two strains of mice (BALB/c and C57BL/6) that exhibit differences in ductal development at sexual maturity and alveologenesis during pregnancy. C57BL/6 mice exhibited reduced proliferative and morphological responses to P. Analysis of known mediators of sidebranching and alveologenesis revealed that reduced P-induced expression of P receptor isoform B and receptor activator of nuclear factor-κB ligand (RANKL), as well as altered expression and regulation of cyclin D1, CCAAT/enhancer binding protein β, and the downstream effectors of RANKL, nuclear Id2 and p21, contribute significantly to the reduced P responsiveness of the C57BL/6 mammary gland. In contrast, E responsiveness was greater in C57BL/6 than in BALB/c glands. E may play a compensatory role in C57BL/6 alveologenesis through its effect on the induction and activation of signal transducer and activator of transcription 5a, a known regulator of RANKL. These observations suggest that in human populations with heterogeneous genetic backgrounds, individuals may respond differentially to the same hormone. Thus, genetic diversity may have a role in determining the effects of P in normal mammary development and tumorigenesis. Reduced progesterone-induced expression of progesterone receptor and RANKL, altered expression and regulation of C/EBPβ, and of the downstream effectors of RANKL, nuclear Id2 and p21, contribute significantly to the reduced progesterone-responsiveness of the C57BL/6 mammary gland compared to the BALB/c gland.

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Essential functions of p21-activated kinase 1 in morphogenesis and differentiation of mammary glands

The Journal of Cell Biology ◽

10.1083/jcb.200212066 ◽

2003 ◽

Vol 161 (3) ◽

pp. 583-592 ◽

Cited By ~ 37

Author(s):

Rui-An Wang ◽

Ratna K. Vadlamudi ◽

Rozita Bagheri-Yarmand ◽

Iwan Beuvink ◽

Nancy E. Hynes ◽

...

Keyword(s):

Mammary Gland ◽

Epithelial Cells ◽

Mammary Gland Development ◽

Mammary Epithelial Cells ◽

Ectopic Expression ◽

Functional Differentiation ◽

Mammary Glands ◽

Pregnancy And Lactation ◽

P21 Activated Kinase ◽

Gland Development

Although growth factors have been shown to influence mammary gland development, the nature of downstream effectors remains elusive. In this study, we show that the expression of p21-activated kinase (Pak)1, a serine/threonine protein kinase, is activated in mammary glands during pregnancy and lactation. By targeting an ectopic expression of a kinase-dead Pak1 mutant under the control of ovine β-lactoglobulin promoter, we found that the mammary glands of female mice expressing kinase-dead Pak1 transgene revealed incomplete lobuloalveolar development and impaired functional differentiation. The expression of whey acidic protein and β-casein and the amount of activated Stat5 in the nuclei of epithelial cells in transgenic mice were drastically reduced. Further analysis of the underlying mechanisms revealed that Pak1 stimulated β-casein promoter activity in normal mouse mammary epithelial cells and also cooperated with Stat5a. Pak1 directly interacted with and phosphorylated Stat5a at Ser 779, and both COOH-terminal deletion containing Ser 779 of Stat5a and the Ser 779 to Ala mutation completely prevented the ability of Pak1 to stimulate β-casein promoter. Mammary glands expressing inactive Pak1 exhibited a reduction of Stat5a Ser 779 phosphorylation. These findings suggest that Pak1 is required for alveolar morphogenesis and lactation function, and thus, identify novel functions of Pak1 in the mammary gland development.

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Signal Transducer and Activator of Transcription 5a Mediates Mammary Ductal Branching and Proliferation in the Nulliparous Mouse

Endocrinology ◽

10.1210/en.2009-1282 ◽

2010 ◽

Vol 151 (6) ◽

pp. 2876-2885 ◽

Cited By ~ 25

Author(s):

Sarah J. Santos ◽

Sandra Z. Haslam ◽

Susan E. Conrad

Keyword(s):

Mammary Gland ◽

Epithelial Cells ◽

Mammary Gland Development ◽

Kinase Inhibitor ◽

Mammary Epithelial Cells ◽

Nuclear Factor Κb ◽

Mammary Glands ◽

Mammary Epithelial ◽

Signal Transducer ◽

Gland Development

Signal transducer and activator of transcription (Stat)5a is a critical regulator of mammary gland development. Previous studies have focused on Stat5a’s role in the late pregnant and lactating gland, and although active Stat5a is detectable in mammary epithelial cells in virgin mice, little is known about its role during early mammary gland development. In this report, we compare mammary gland morphology in pubertal and adult nulliparous wild-type and Stat5a−/− mice. The Stat5a-null mammary glands exhibited defects in secondary and side branching, providing evidence that Stat5a regulates these processes. In addition, Stat5a−/− mammary glands displayed an attenuated proliferative response to pregnancy levels of estrogen plus progesterone (E+P), suggesting that it plays an important role in early pregnancy. Finally, we examined one potential mediator of Stat5a’s effects, receptor activator of nuclear factor-κB ligand (RANKL). Stat5a−/− mammary glands were defective in inducing RANKL in response to E+P treatment. In addition, regulation of several reported RANKL targets, including inhibitor of DNA binding 2 (Id2), cyclin D1, and the cyclin-dependent kinase inhibitor p21Waf1/Cip1, was altered in Stat5a−/− mammary cells, suggesting that one or more of these proteins mediate the effects of Stat5a in E+P-treated mammary epithelial cells.

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Food intake dependent and independent effects of heat stress on lactation and mammary gland development

10.1101/2020.04.03.024679 ◽

2020 ◽

Author(s):

Yao Xiao ◽

Jason M. Kronenfeld ◽

Benjamin J. Renquist

Keyword(s):

Heat Stress ◽

Mammary Gland ◽

Food Intake ◽

Milk Production ◽

Mammary Gland Development ◽

Heat Exposure ◽

Mammary Development ◽

Late Gestation ◽

Independent Effects ◽

Gland Development

ABSTRACTWith a growing population, a reliable food supply is increasingly important. Heat stress reduces livestock meat and milk production. Genetic selection of high producing animals increases endogenous heat production, while climate change increases exogenous heat exposure. Both sources of heat exacerbate the risk of heat-induced depression of production. Rodents are valuable models to understand mechanisms conserved across species. Heat exposure suppresses feed intake across homeothermic species including rodents and production animal species. We assessed the response to early-mid lactation or late gestation heat exposure on milk production and mammary gland development/function, respectively. Using pair-fed controls we experimentally isolated the food intake dependent and independent effects of heat stress on mammary function and mass. Heat exposure (35°C, relative humidity 50%) decreased daily food intake. When heat exposure occurred during lactation, hypophagia accounted for approximately 50% of the heat stress induced hypogalactia. Heat exposure during middle to late gestation suppressed food intake, which was fully responsible for the lowered mammary gland weight of dams at parturition. However, the impaired mammary gland function in heat exposed dams measured by metabolic rate and lactogenesis could not be explained by depressed food consumption. In conclusion, mice recapitulate the depressed milk production and mammary gland development observed in dairy species while providing insight regarding the role of food intake. This opens the potential to apply genetic, experimental and pharmacological models unique to mice to identify the mechanism by which heat is limiting animal production.Summary StatementsThis study demonstrates that heat stress decreases lactation and mammary development through food intake dependent and independent mechanisms.

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Baicalin Promotes Mammary Gland Development via Steroid-Like Activities

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.682469 ◽

2021 ◽

Vol 9 ◽

Author(s):

Weizhen Chen ◽

Wei Wei ◽

Liya Yu ◽

Xin Zhang ◽

Fujing Huang ◽

...

Keyword(s):

Mammary Gland ◽

Tumor Growth ◽

Cell Line ◽

Cancer Progression ◽

Mammary Gland Development ◽

Biological Activities ◽

Xenograft Model ◽

Mammary Development ◽

Tumor Xenograft ◽

Gland Development

Baicalin, the main flavonoid component extracted from Scutellaria roots, has a variety of biological activities and is therefore used in the treatment of many kinds of diseases. However, whether baicalin affects the normal development of tissues and organs is still unclear. Here, using a mouse mammary gland model, we investigated the effects of baicalin on the expansion of mammary stem cells (MaSCs) and mammary development, as well as breast cancer progression. Interestingly, we found that baicalin administration significantly accelerates duct elongation at puberty, and promotes alveolar development and facilitates milk secretion during pregnancy. Furthermore, self-renewal of MaSCs was significantly promoted in the presence of baicalin. Moreover, in a tumor xenograft model, baicalin promoted tumor growth of the MDA-MB-231 cell line, but suppressed tumor growth of the ZR-751 cell line. Mechanistically, baicalin can induce expression of the protein C receptor, while inhibiting the expression of the estrogen receptor. Transcriptome analysis revealed that baicalin is involved in signaling pathways related to mammary gland development, immune response, and cell cycle control. Taken together, our results from comprehensive investigation of the biological activity of baicalin provide a theoretical basis for its rational clinical application.

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Chromosomal mapping and quantitative analysis of estrogen-related receptor alpha-1, estrogen receptors alpha and beta and progesterone receptor in the bovine mammary gland

Journal of Endocrinology ◽

10.1677/joe.1.06139 ◽

2005 ◽

Vol 185 (3) ◽

pp. 593-603 ◽

Cited By ~ 31

Author(s):

E E Connor ◽

D L Wood ◽

T S Sonstegard ◽

A F da Mota ◽

G L Bennett ◽

...

Keyword(s):

Mammary Gland ◽

Progesterone Receptor ◽

Estrogen Receptors ◽

Mammary Gland Development ◽

Chromosomal Mapping ◽

Mammary Tissue ◽

Bovine Mammary Gland ◽

Receptor Alpha ◽

Gland Development ◽

Estrogen Related Receptor

Steroid receptors are key transcriptional regulators of mammary growth, development and lactation. Expression of estrogen receptors alpha (ERα) and beta (ERβ), progesterone receptor (PR), and estrogen-related receptor alpha-1 (ERRβ) have been evaluated in bovine mammary gland. The ERRα is an orphan receptor that, in other species and tissues, appears to function in the regulation of estrogen-response genes including lactoferrin and medium chain acyl-CoA dehydrogenase and in mitochondrial biogenesis. Expression of ERα, ERβ, PR and ERRα was characterized in mammary tissue obtained from multiple stages of bovine mammary gland development using quantitative real-time RT-PCR. Expression was evaluated in prepubertal heifers, primigravid cows, lactating non-pregnant cows, lactating pregnant cows and non-lactating pregnant cows (n=4 to 9 animals/stage). In addition, ERα, ERβ, PR and ERRα were mapped to chromosomes 9, 10, 15 and 29 respectively, by linkage and radiation hybrid mapping. Results indicated that expression of ERα, PR and ERRα was largely coordinately regulated and they were present in significant quantity during all physiological stages evaluated. In contrast, ERβ transcripts were present at a very low concentration during all stages. Furthermore, no ERβ protein could be detected in bovine mammary tissue by immunohistochemistry. The ERα and PR proteins were detected during all physiological states, including lactation. Our results demonstrate the presence of ERα, PR and ERRα during all physiological stages, and suggest a functional role for ERRα and a relative lack of a role for ERβ in bovine mammary gland development and lactation.

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