scholarly journals Essential function of Wnt-4 in mammary gland development downstream of progesterone signaling

2000 ◽  
Vol 14 (6) ◽  
pp. 650-654 ◽  
Author(s):  
Cathrin Brisken ◽  
Anna Heineman ◽  
Tony Chavarria ◽  
Brian Elenbaas ◽  
Jian Tan ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Mammary Epithelial Cells ◽  
Ectopic Expression ◽  
Mammary Epithelium ◽  
Reproductive Hormones ◽  
Mammary Epithelial ◽  
Mammary Gland Morphogenesis ◽  
Mammary Epithelia ◽  
Gland Morphogenesis ◽  
Gland Development

Female reproductive hormones control mammary gland morphogenesis. In the absence of the progesterone receptor (PR) from the mammary epithelium, ductal side-branching fails to occur. We can overcome this defect by ectopic expression of the protooncogene Wnt-1. Transplantation of mammary epithelia fromWnt-4−/− mice shows that Wnt-4 has an essential role in side-branching early in pregnancy. PR andWnt-4 mRNAs colocalize to the luminal compartment of the ductal epithelium. Progesterone induces Wnt-4 in mammary epithelial cells and is required for increased Wnt-4 expression during pregnancy. Thus, Wnt signaling is essential in mediating progesterone function during mammary gland morphogenesis.

scholarly journals Cyclin-Dependent Kinase Inhibitor P27Kip1 Is Required for Mouse Mammary Gland Morphogenesis and Function

2001 ◽  
Vol 153 (5) ◽  
pp. 917-932 ◽  
Author(s):  
Rebecca S. Muraoka ◽  
Anne E.G. Lenferink ◽  
Jean Simpson ◽  
Dana M. Brantley ◽  
L. Renee Roebuck ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Cyclin D1 ◽  
Mammary Epithelial Cells ◽  
Mammary Glands ◽  
Mammary Epithelial ◽  
Cyclin Dependent Kinase ◽  
Wild Type ◽  
Mammary Gland Morphogenesis ◽  
Ductal Branching ◽  
Gland Morphogenesis

We have studied the role of the cyclin-dependent kinase (Cdk) inhibitor p27Kip1 in postnatal mammary gland morphogenesis. Based on its ability to negatively regulate cyclin/Cdk function, loss of p27 may result in unrestrained cellular proliferation. However, recent evidence about the stabilizing effect of p27 on cyclin D1–Cdk4 complexes suggests that p27 deficiency might recapitulate the hypoplastic mammary phenotype of cyclin D1–deficient animals. These hypotheses were investigated in postnatal p27-deficient (p27−/−), hemizygous (p27+/−), or wild-type (p27+/+) mammary glands. Mammary glands from p27+/− mice displayed increased ductal branching and proliferation with delayed postlactational involution. In contrast, p27−/− mammary glands or wild-type mammary fat pads reconstituted with p27−/− epithelium produced the opposite phenotype: hypoplasia, low proliferation, decreased ductal branching, impaired lobuloalveolar differentiation, and inability to lactate. The association of cyclin D1 with Cdk4, the kinase activity of Cdk4 against pRb in vitro, the nuclear localization of cyclin D1, and the stability of cyclin D1 were all severely impaired in p27−/− mammary epithelial cells compared with p27+/+ and p27+/− mammary epithelial cells. Therefore, p27 is required for mammary gland development in a dose-dependent fashion and positively regulates cyclin D–Cdk4 function in the mammary gland.

scholarly journals Fine-tuning of Epithelial EGFR signals Supports Coordinated Mammary Gland Development

2020 ◽  
Author(s):  
Alexandr Samocha ◽  
Hanna M. Doh ◽  
Vaishnavi Sitarama ◽  
Quy H. Nguyen ◽  
Oghenekevwe Gbenedio ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Mammary Epithelial Cells ◽  
Mammary Epithelium ◽  
Gene Signature ◽  
Mammary Epithelial ◽  
Fine Tuning ◽  
Basal Cells ◽  
Stem And Progenitor Cells

SummaryDuring puberty, robust morphogenesis occurs in the mammary gland; stem- and progenitor-cells develop into mature basal- and luminal-cells to form the ductal tree. The receptor signals that govern this process in mammary epithelial cells (MECs) are incompletely understood. The EGFR has been implicated and here we focused on EGFR’s downstream pathway component Rasgrp1. We find that Rasgrp1 dampens EGF-triggered signals in MECs. Biochemically and in vitro, Rasgrp1 perturbation results in increased EGFR-Ras-PI3K-AKT and mTORC1-S6 kinase signals, increased EGF-induced proliferation, and aberrant branching-capacity in 3D cultures. However, in vivo, Rasgrp1 perturbation results in delayed ductal tree maturation with shortened branches and reduced cellularity. Rasgrp1-deficient MEC organoids revealed lower frequencies of basal cells, the compartment that incorporates stem cells. Molecularly, EGF effectively counteracts Wnt signal-driven stem cell gene signature in organoids. Collectively, these studies demonstrate the need for fine-tuning of EGFR signals to properly instruct mammary epithelium during puberty.

scholarly journals p19ARFDetermines the Balance between Normal Cell Proliferation Rate and Apoptosis during Mammary Gland Development

2004 ◽  
Vol 15 (5) ◽  
pp. 2302-2311 ◽  
Author(s):  
Yijun Yi ◽  
Anne Shepard ◽  
Frances Kittrell ◽  
Biserka Mulac-Jericevic ◽  
Daniel Medina ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Mammary Gland ◽  
Epithelial Cells ◽  
Protein Level ◽  
Normal Cell ◽  
Mammary Gland Development ◽  
Mammary Epithelial Cells ◽  
Mammary Epithelial ◽  
Proliferation Rate ◽  
Gland Development

This study demonstrated, for the first time, the following events related to p19ARFinvolvement in mammary gland development: 1) Progesterone appears to regulate p19ARFin normal mammary gland during pregnancy. 2) p19ARFexpression levels increased sixfold during pregnancy, and the protein level plateaus during lactation. 3) During involution, p19ARFprotein level remained at high levels at 2 and 8 days of involution and then, declined sharply at day 15. Absence of p19ARFin mammary epithelial cells leads to two major changes, 1) a delay in the early phase of involution concomitant with downregulation of p21Cip1and decrease in apoptosis, and 2) p19ARFnull cells are immortal in vivo measured by serial transplantion, which is partly attributed to complete absence of p21Cip1compared with WT cells. Although, p19ARFis dispensable in mammary alveologenesis, as evidenced by normal differentiation in the mammary gland of pregnant p19ARFnull mice, the upregulation of p19ARFby progesterone in the WT cells and the weakness of p21Cip1in mammary epithelial cells lacking p19ARFstrongly suggest that the functional role(s) of p19ARFin mammary gland development is critical to sustain normal cell proliferation rate during pregnancy and normal apoptosis in involution possibly through the p53-dependent pathway.

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

2003 ◽  
Vol 161 (3) ◽  
pp. 583-592 ◽  
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.

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

Endocrinology ◽  
2010 ◽  
Vol 151 (6) ◽  
pp. 2876-2885 ◽  
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.

Vitamin D3 receptor ablation alters mammary gland morphogenesis

Development ◽  
2002 ◽  
Vol 129 (13) ◽  
pp. 3067-3076
Author(s):  
Glendon Zinser ◽  
Kathryn Packman ◽  
JoEllen Welsh
Keyword(s):  
Mammary Gland ◽  
Vitamin D3 ◽  
Stromal Cells ◽  
Knockout Mice ◽  
Wild Type ◽  
Dihydroxyvitamin D3 ◽  
Mammary Gland Morphogenesis ◽  
Gland Morphogenesis ◽  
Gland Development

Postnatal mammary gland morphogenesis is achieved through coordination of signaling networks in both the epithelial and stromal cells of the developing gland. While the major proliferative hormones driving pubertal mammary gland development are estrogen and progesterone, studies in transgenic and knockout mice have successfully identified other steroid and peptide hormones that impact on mammary gland development. The vitamin D3 receptor (VDR), whose ligand 1,25-dihydroxyvitamin D3 is the biologically active form of vitamin D3, has been implicated in control of differentiation, cell cycle and apoptosis of mammary cells in culture, but little is known about the physiological relevance of the vitamin D3 endocrine system in the developing gland. In these studies, we report the expression of the VDR in epithelial cells of the terminal end bud and subtending ducts, in stromal cells and in a subset of lymphocytes within the lymph node. In the terminal end bud, a distinct gradient of VDR expression is observed, with weak VDR staining in proliferative populations and strong VDR staining in differentiated populations. The role of the VDR in ductal morphogenesis was examined in Vdr knockout mice fed high dietary Ca2+ which normalizes fertility, serum estrogen and neonatal growth. Our results indicate that mammary glands from virgin Vdr knockout mice are heavier and exhibit enhanced growth, as evidenced by higher numbers of terminal end buds, greater ductal outgrowth and enhanced secondary branch points, compared with glands from age- and weight-matched wild-type mice. In addition, glands from Vdr knockout mice exhibit enhanced growth in response to exogenous estrogen and progesterone, both in vivo and in organ culture, compared with glands from wild-type mice. Our data provide the first in vivo evidence that 1,25-dihydroxyvitamin D3 and the VDR impact on ductal elongation and branching morphogenesis during pubertal development of the mammary gland. Collectively, these results suggest that the vitamin D3 signaling pathway participates in negative growth regulation of the mammary gland.

Conditional loss of PTEN leads to precocious development and neoplasia in the mammary gland

Development ◽  
2002 ◽  
Vol 129 (17) ◽  
pp. 4159-4170 ◽  
Author(s):  
Gang Li ◽  
Gertraud W. Robinson ◽  
Ralf Lesche ◽  
Hilda Martinez-Diaz ◽  
Zhaorong Jiang ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Epithelial Cells ◽  
Mammary Epithelial Cells ◽  
Mammary Epithelial ◽  
Pten Gene ◽  
Mammary Tissue ◽  
Breast Cancers ◽  
Gene Mutant ◽  
Mammary Epithelia ◽  
Ductal Branching

PTEN tumor suppressor is frequently mutated in human cancers, including breast cancers. Female patients with inherited PTEN mutations suffer from virginal hypertrophy of the breast with high risk of malignant transformation. However, the exact mechanisms of PTEN in controlling mammary gland development and tumorigenesis are unclear. In this study, we generated mice with a mammary-specific deletion of the Pten gene. Mutant mammary tissue displayed precocious lobulo-alveolar development, excessive ductal branching, delayed involution and severely reduced apoptosis. Pten null mammary epithelial cells were disregulated and hyperproliferative. Mutant females developed mammary tumors early in life. Similar phenotypes were observed in Pten-null mammary epithelia that had been transplanted into wild-type stroma, suggesting that PTEN plays an essential and cell-autonomous role in controlling the proliferation, differentiation and apoptosis of mammary epithelial cells.

scholarly journals Insights into the role of connexins in mammary gland morphogenesis and function

Reproduction ◽  
2015 ◽  
Vol 149 (6) ◽  
pp. R279-R290 ◽  
Author(s):  
Michael K G Stewart ◽  
Jamie Simek ◽  
Dale W Laird
Keyword(s):  
Mammary Gland ◽  
Gap Junctions ◽  
Normal Tissue ◽  
Mammary Gland Development ◽  
Mammary Gland Morphogenesis ◽  
Gland Morphogenesis ◽  
Cell Death Mechanisms ◽  
And Function ◽  
Gland Development

Gap junctions formed of connexin subunits link adjacent cells by direct intercellular communication that is essential for normal tissue homeostasis in the mammary gland. The mammary gland undergoes immense remodeling and requires exquisite regulation to control the proliferative, differentiating, and cell death mechanisms regulating gland development and function. The generation of novel genetically modified mice with reduced or ablated connexin function within the mammary gland has advanced our understanding of the role of gap junctions during the complex and dynamic process of mammary gland development. These studies have revealed an important stage-specific role for Cx26 (GJA1) and Cx43 (GJB2), while Cx30 (GJB6) and Cx32 (Gjb1) can be eliminated without compromising the gland. Yet, there remain gaps in our understanding of the role of mammary gland gap junctions.

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