scholarly journals Steroid Receptor Coactivator 2 is Required for Female Fertility and Mammary Morphogenesis: Insights from the Mouse, Relevance to the Human

2007 ◽  
Vol 5 (1) ◽  
pp. nrs.05011 ◽  
Author(s):  
Atish Mukherjee ◽  
Paula Amato ◽  
D. Craig Allred ◽  
Francesco J. DeMayo ◽  
John P. Lydon
Keyword(s):  
Mammary Gland ◽  
Gene Knockout ◽  
Embryo Implantation ◽  
Cell Types ◽  
Steroid Receptor ◽  
Branching Morphogenesis ◽  
Mammary Epithelial ◽  
Signaling Cascades ◽  
Steroid Receptor Coactivator ◽  
Female Reproductive Health

Although the importance of the progesterone receptor (PR) to female reproductive and mammary gland biology is firmly established, the coregulators selectively co-opted by PR in these systems have not been clearly delineated. A selective gene-knockout approach applied to the mouse, which abrogates gene function only in cell types that express PR, recently disclosed steroid receptor coactivator 2 (SRC-2, also known as TIF-2 or GRIP-1) to be an indispensable coregulator for uterine and mammary gland responses that require progesterone. Uterine cells positive for PR (but devoid of SRC-2) were found to be incapable of facilitating embryo implantation, a necessary first step toward the establishment of the materno-fetal interface. Importantly, such an implantation defect is not exhibited by knockouts for SRC-1 or SRC-3, underscoring the unique coregulator importance of SRC-2 in peri-implantation biology. Moreover, despite normal levels of PR, SRC-1 and SRC-3, progesterone-dependent branching morphogenesis and alveologenesis fails to occur in the murine mammary gland in the absence of SRC-2, thereby establishing a critical coregulator role for SRC-2 in signaling cascades that mediate progesterone-induced mammary epithelial proliferation. Finally, the recent detection of SRC-2 in the human endometrium and breast suggests that this coregulator may represent a new clinical target for the future management of female reproductive health and/or breast cancer.

scholarly journals Steroid Receptor Coactivator 2 Is Critical for Progesterone-Dependent Uterine Function and Mammary Morphogenesis in the Mouse

2006 ◽  
Vol 26 (17) ◽  
pp. 6571-6583 ◽  
Author(s):  
Atish Mukherjee ◽  
Selma M. Soyal ◽  
Rodrigo Fernandez-Valdivia ◽  
Martine Gehin ◽  
Pierre Chambon ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Embryo Implantation ◽  
Steroid Receptor ◽  
Ovarian Activity ◽  
Mouse Uterus ◽  
Steroid Receptor Coactivator ◽  
Mammary Morphogenesis ◽  
Uterine Function ◽  
And Function

ABSTRACT Although the essential involvement of the progesterone receptor (PR) in female reproductive tissues is firmly established, the coregulators preferentially enlisted by PR to mediate its physiological effects have yet to be fully delineated. To further dissect the roles of members of the steroid receptor coactivator (SRC)/p160 family in PR-mediated reproductive processes in vivo, state-of-the-art cre-loxP engineering strategies were employed to generate a mouse model (PR Cre/+ SRC-2 flox/flox) in which SRC-2 function was abrogated only in cell lineages that express the PR. Fertility tests revealed that while ovarian activity was normal, PR Cre/+ SRC-2 flox/flox mouse uterine function was severely compromised. Absence of SRC-2 in PR-positive uterine cells was shown to contribute to an early block in embryo implantation, a phenotype not shared by SRC-1 or -3 knockout mice. In addition, histological and molecular analyses revealed an inability of the PR Cre/+ SRC-2 flox/flox mouse uterus to undergo the necessary cellular and molecular changes that precede complete P-induced decidual progression. Moreover, removal of SRC-1 in the PR Cre/+ SRC-2 flox/flox mouse uterus resulted in the absence of a decidual response, confirming that uterine SRC-2 and -1 cooperate in P-initiated transcriptional programs which lead to full decidualization. In the case of the mammary gland, whole-mount and histological analysis disclosed the absence of significant ductal side branching and alveologenesis in the hormone-treated PR Cre/+ SRC-2 flox/flox mammary gland, reinforcing an important role for SRC-2 in cellular proliferative changes that require PR. We conclude that SRC-2 is appropriated by PR in a subset of transcriptional cascades obligate for normal uterine and mammary morphogenesis and function.

Postnatal mammary gland development requires macrophages and eosinophils

Development ◽  
2000 ◽  
Vol 127 (11) ◽  
pp. 2269-2282 ◽  
Author(s):  
V. Gouon-Evans ◽  
M.E. Rothenberg ◽  
J.W. Pollard
Keyword(s):  
Mammary Gland ◽  
Postnatal Development ◽  
Cell Types ◽  
Branching Morphogenesis ◽  
Mammary Epithelial ◽  
Null Mutation ◽  
Eosinophil Recruitment ◽  
Terminal End Buds ◽  
Branch Formation ◽  
Local Recruitment

Interactions between mammary epithelial and mesenchymal cells including fibroblasts and adipocytes are crucial for the proper postnatal development of the mammary ductal tree. Often overlooked, however, are the migrant cells that enter tissues at different stages of development. In this paper we identify two such cell types, macrophages and eosinophils, that are recruited around the growing terminal end buds (TEBs) during postnatal development. An important role for leukocytes in mammary gland ductal outgrowth is first demonstrated by depleting mice of leukocytes using sub-lethal (gamma)-irradiation. This treatment results in a curtailment of mammary gland epithelial development that is completely rescued by bone-marrow transplantation, concurrent with a restoration of macrophage and eosinophil recruitment around the growing ducts. Using mice homozygous for a null mutation in the gene for CSF1 (Csfm(op)/Csfm(op)), the major growth factor for macrophages, we show that in the absence of CSF1, the population of macrophages in mammary glands is depleted. In this mutant, the formation of TEBs, their outgrowth into the fat pad and the branching of the resultant ducts are all impaired. Similarly, by using mice homozygous for a null mutation in the gene for eotaxin, a major chemokine for local recruitment of eosinophils in tissue, we identify eotaxin as the necessary and sufficient chemokine responsible for eosinophil recruitment around TEBs. In the absence of eosinophils, mammary gland branch formation and to a lesser extent TEB formation are reduced. Our data show that CSF1-regulated macrophages, in collaboration with eotaxin-regulated eosinophils, have essential and complementary functions in regulating the branching morphogenesis of the mammary gland.

scholarly journals The LIM Domain Protein Lmo4 Is Highly Expressed in Proliferating Mouse Epithelial Tissues

2005 ◽  
Vol 53 (4) ◽  
pp. 475-486 ◽  
Author(s):  
Eleanor Y.M. Sum ◽  
Lorraine A. O'Reilly ◽  
Nadeen Jonas ◽  
Geoffrey J. Lindeman ◽  
Jane E. Visvader
Keyword(s):  
Small Intestine ◽  
Mammary Gland ◽  
Cell Types ◽  
Mammary Epithelial ◽  
Specific Cell ◽  
Basal Cells ◽  
Proliferating Cells ◽  
Terminal End Buds ◽  
Mouse Tissues ◽  
Important Regulator

LMO4 belongs to the LIM-only family of zinc finger proteins that have been implicated in oncogenesis. The LMO4 gene is overexpressed in breast cancer and oral cavity carcinomas, and high levels of this protein inhibit mammary epithelial differentiation. Targeted deletion of Lmo4 in mice leads to complex phenotypic abnormalities and perinatal lethality. To further understand the role of LMO4, we have characterized Lmo4 expression in adult mouse tissues by immunohistochemical staining using monoclonal anti-Lmo4 antibodies. Lmo4 was highly expressed within specific cell types in diverse tissues. Expression was prevalent in epithelial-derived tissues, including the mammary gland, tongue, skin, small intestine, lung, and brain. High levels of Lmo4 were frequently observed in proliferating cells, such as the crypt cells of the small intestine and the basal cells of the skin and tongue. Lmo4 was highly expressed in the proliferative cap cell layer of the terminal end buds in the peripubertal mammary gland and in the lobuloalveolar units during pregnancy. The expression profile of Lmo4 suggests that this cofactor is an important regulator of epithelial proliferation and has implications for its role in the pathogenicity of cancer.

scholarly journals Minireview: Steroid Receptor Coactivator-3: A Multifarious Coregulator in Mammary Gland Metastasis

Endocrinology ◽  
2011 ◽  
Vol 152 (1) ◽  
pp. 19-25 ◽  
Author(s):  
John P. Lydon ◽  
Bert W. O'Malley
Keyword(s):  
Mammary Gland ◽  
Growth Factor ◽  
Tumor Cell ◽  
Primary Tumor ◽  
Steroid Receptor ◽  
Tumor Formation ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Steroid Receptor Coactivator ◽  
Tumor Cell Motility

Abstract A member of the steroid receptor coactivator (SRC)/p160 family, SRC-3 acts as a coregulator for nuclear receptor (NR) and non-NR transcription factors. Such coregulator pleiotropy enables SRC-3 to influence a myriad of signaling networks that are essential for normal physiology and pathophysiology. Although SRC-3’s proliferative role in primary tumor formation in the mammary gland is well established, a role for this oncogenic coregulator in tumor cell motility and invasion has only recently been elucidated. In the nucleus, SRC-3 is required for the execution of the epithelial–mesenchymal transition, a programming step which endows an immotile cancer cell with motile and invasive characteristics. Nuclear SRC-3 is also essential for proteolytic breakdown of the extracellular matrix by matrix-metalloproteinases, a process which enables primary tumor cell invasion into the surrounding stroma. At the plasma membrane, however, a truncated isoform of SRC-3 (SRC-3Δ4) serves as a signaling adaptor for the epidermal growth factor→focal adhesion kinase→c-Src signal transduction pathway, a signaling cascade that is central to growth factor–induced cell migration and invasion. Together, these studies underscore a pivotal role for SRC-3 not only as a proto-oncogene but also as a prometastatic factor during the early steps in the invasion-metastasis cascade. Beyond furnishing critical mechanistic insights into SRC-3’s involvement in mammary tumor progression, these findings provide opportunities to develop new approaches for breast cancer diagnosis and intervention.

scholarly journals The interplay of matrix metalloproteinases, morphogens and growth factors is necessary for branching of mammary epithelial cells

Development ◽  
2001 ◽  
Vol 128 (16) ◽  
pp. 3117-3131 ◽  
Author(s):  
Marina Simian ◽  
Yohei Hirai ◽  
Marc Navre ◽  
Zena Werb ◽  
Andre Lochter ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Growth Factors ◽  
Growth Factor ◽  
Epithelial Cell ◽  
Fibroblast Growth Factor ◽  
Mammary Epithelial Cell ◽  
Three Dimensional ◽  
Branching Morphogenesis ◽  
Mammary Epithelial ◽  
Fibroblast Growth

The mammary gland develops its adult form by a process referred to as branching morphogenesis. Many factors have been reported to affect this process. We have used cultured primary mammary epithelial organoids and mammary epithelial cell lines in three-dimensional collagen gels to elucidate which growth factors, matrix metalloproteinases (MMPs) and mammary morphogens interact in branching morphogenesis. Branching stimulated by stromal fibroblasts, epidermal growth factor, fibroblast growth factor 7, fibroblast growth factor 2 and hepatocyte growth factor was strongly reduced by inhibitors of MMPs, indicating the requirement of MMPs for three-dimensional growth involved in morphogenesis. Recombinant stromelysin 1/MMP3 alone was sufficient to drive branching in the absence of growth factors in the organoids. Plasmin also stimulated branching; however, plasmin-dependent branching was abolished by both inhibitors of plasmin and MMPs, suggesting that plasmin activates MMPs. To differentiate between signals for proliferation and morphogenesis, we used a cloned mammary epithelial cell line that lacks epimorphin, an essential mammary morphogen. Both epimorphin and MMPs were required for morphogenesis, but neither was required for epithelial cell proliferation. These results provide direct evidence for a crucial role of MMPs in branching in mammary epithelium and suggest that, in addition to epimorphin, MMP activity is a minimum requirement for branching morphogenesis in the mammary gland.

scholarly journals Site-specific inductive and inhibitory activities of MMP-2 and MMP-3 orchestrate mammary gland branching morphogenesis

2003 ◽  
Vol 162 (6) ◽  
pp. 1123-1133 ◽  
Author(s):  
Bryony S. Wiseman ◽  
Mark D. Sternlicht ◽  
Leif R. Lund ◽  
Caroline M. Alexander ◽  
Joni Mott ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Branching Morphogenesis ◽  
Mammary Epithelial ◽  
Fat Pad ◽  
Point Selection ◽  
Site Specific ◽  
Lateral Branching ◽  
Mammary Fat Pad ◽  
Epithelial Cell Apoptosis ◽  
Inhibitory Activities

During puberty, mouse mammary epithelial ducts invade the stromal mammary fat pad in a wave of branching morphogenesis to form a complex ductal tree. Using pharmacologic and genetic approaches, we find that mammary gland branching morphogenesis requires transient matrix metalloproteinase (MMP) activity for invasion and branch point selection. MMP-2, but not MMP-9, facilitates terminal end bud invasion by inhibiting epithelial cell apoptosis at the start of puberty. Unexpectedly, MMP-2 also represses precocious lateral branching during mid-puberty. In contrast, MMP-3 induces secondary and tertiary lateral branching of ducts during mid-puberty and early pregnancy. Nevertheless, the mammary gland is able to develop lactational competence in MMP mutant mice. Thus, specific MMPs refine the mammary branching pattern by distinct mechanisms during mammary gland branching morphogenesis.

The EGF-CFC family: novel epidermal growth factor-related proteins in development and cancer.

2000 ◽  
pp. 199-226 ◽  
Author(s):  
D S Saloman ◽  
C Bianco ◽  
A D Ebert ◽  
N I Khan ◽  
M De Santis ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Growth Factor ◽  
Epithelial Cells ◽  
Mammary Epithelial Cells ◽  
Branching Morphogenesis ◽  
Mammary Epithelial ◽  
Biologically Active ◽  
Beta Catenin ◽  
Mesenchymal Transition ◽  
Related Proteins

The EGF-CFC gene family encodes a group of structurally related proteins that serve as important competence factors during early embryogenesis in Xenopus, zebrafish, mice and humans. This multigene family consists of Xenopus FRL-1, zebrafish one-eyed-pinhead (oep), mouse cripto (Cr-1) and cryptic, and human cripto (CR-1) and criptin. FRL-1, oep and mouse cripto are essential for the formation of mesoderm and endoderm and for correct establishment of the anterior/posterior axis. In addition, oep and cryptic are important for the establishment of left-right (L/R) asymmetry. In zebrafish, there is strong genetic evidence that oep functions as an obligatory co-factor for the correct signaling of a transforming growth factor-beta (TGFbeta)-related gene, nodal, during gastrulation and during L/R asymmetry development. Expression of Cr-1 and cryptic is extinguished in the embryo after day 8 of gestation except for the developing heart where Cr-1 expression is necessary for myocardial development. In the mouse, cryptic is not expressed in adult tissues whereas Cr-1 is expressed at a low level in several different tissues including the mammary gland. In the mammary gland, expression of Cr-1 in the ductal epithelial cells increases during pregnancy and lactation and immunoreactive and biologically active Cr-1 protein can be detected in human milk. Overexpression of Cr-1 in mouse mammary epithelial cells can facilitate their in vitro transformation and in vivo these Cr-1-transduced cells produce ductal hyperplasias in the mammary gland. Recombinant mouse or human cripto can enhance cell motility and branching morphogenesis in mammary epithelial cells and in some human tumor cells. These effects are accompanied by an epithelial-mesenchymal transition which is associated with a decrease in beta-catenin function and an increase in vimentin expression. Expression of cripto is increased several-fold in human colon, gastric, pancreatic and lung carcinomas and in a variety of different types of mouse and human breast carcinomas. More importantly, this increase can first be detected in premalignant lesions in some of these tissues. Although a specific receptor for the EGF-CFC proteins has not yet been identified, oep depends upon an activin-type RIIB and RIB receptor system that functions through Smad-2. Mouse and human cripto have been shown to activate a ras/raf/MAP kinase signaling pathway in mammary epithelial cells. Activation of phosphatidylinositol 3-kinase and Akt are also important for the ability of CR-1 to stimulate cell migration and to block lactogenic hormone-induced expression of beta-casein and whey acidic protein. In mammary epithelial cells, part of these responses may depend on the ability of CR-1 to transactivate erb B-4 and/or fibroblast growth factor receptor 1 through an src-like tyrosine kinase.

Rescue of the parathyroid hormone-related protein knockout mouse demonstrates that parathyroid hormone-related protein is essential for mammary gland development

Development ◽  
1998 ◽  
Vol 125 (7) ◽  
pp. 1285-1294 ◽  
Author(s):  
J.J. Wysolmerski ◽  
W.M. Philbrick ◽  
M.E. Dunbar ◽  
B. Lanske ◽  
H. Kronenberg ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Parathyroid Hormone ◽  
Epithelial Cells ◽  
Mammary Epithelial Cells ◽  
Branching Morphogenesis ◽  
Mammary Epithelial ◽  
Related Protein ◽  
Transgenic Expression ◽  
Parathyroid Hormone Related Protein ◽  
Pthrp Receptor

Parathyroid hormone-related protein (PTHrP) was originally discovered as a tumor product that causes humoral hypercalcemia of malignancy. PTHrP is now known to be widely expressed in normal tissues and growing evidence suggests that it is an important developmental regulatory molecule. We had previously reported that overexpression of PTHrP in the mammary glands of transgenic mice impaired branching morphogenesis during sexual maturity and early pregnancy. We now demonstrate that PTHrP plays a critical role in the epithelial-mesenchymal communications that guide the initial round of branching morphogenesis that occurs during the embryonic development of the mammary gland. We have rescued the PTHrP-knockout mice from neonatal death by transgenic expression of PTHrP targeted to chondrocytes. These rescued mice are devoid of mammary epithelial ducts. We show that disruption of the PTHrP gene leads to a failure of the initial round of branching growth that is responsible for transforming the mammary bud into the rudimentary mammary duct system. In the absence of PTHrP, the mammary epithelial cells degenerate and disappear. The ability of PTHrP to support embryonic mammary development is a function of amino-terminal PTHrP, acting via the PTH/PTHrP receptor, for ablation of the PTH/PTHrP receptor gene recapitulates the phenotype of PTHrP gene ablation. We have localized PTHrP expression to the embryonic mammary epithelial cells and PTH/PTHrP receptor expression to the mammary mesenchyme using in situ hybridization histochemistry. Finally, we have rescued mammary gland development in PTHrP-null animals by transgenic expression of PTHrP in embryonic mammary epithelial cells. We conclude that PTHrP is a critical epithelial signal received by the mammary mesenchyme and involved in supporting the initiation of branching morphogenesis.

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