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Molecular mechanisms guiding embryonic mammary gland development

Cowin, Pamela; Wysolmerski, John
The mammary gland is an epidermal appendage that begins to form during embryogenesis, but whose development is only completed during pregnancy. Each mammary gland begins as a budlike invagination of the surface ectoderm, which then gives rise to a simple duct system by birth. Subsequent development occurs during sexual maturation and during pregnancy and lactation. In this review, we outline the distinct stages of embryonic mammary development and discuss the molecular pathways involved in the regulation of morphogenesis at each stage. We also discuss the potential relevance of embryonic breast development to the pathophysiology of breast cancer and highlight questions for future research
PMCID:2869520
PMID: 20484386
ISSN: 1943-0264
CID: 109851

Choreographing Metastasis to the Tune of LTBP

Chandramouli, Anupama; Simundza, Julia; Pinderhughes, Alicia; Cowin, Pamela
Latent Transforming Growth Factor beta (TGFbeta) Binding Proteins (LTBPs) are chaperones and determinants of TGFbeta isoform-specific secretion. They belong to the LTBP/Fibrillin family and form integral components of the fibronectin and microfibrillar extracellular matrix (ECM). LTBPs serve as master regulators of TGFbeta bioavailability, functioning to incorporate and spatially pattern latent TGFbeta at regular intervals within the ECM, and actively participate in integrin-mediated stretch activation of TGFbeta in vivo. In so doing they create a highly patterned sensory system where local changes in ECM tension can be detected and transduced into focal signals. The physiological role of LTBPs in the mammary gland remains largely unstudied, however both loss and gain of LTBP expression is found in breast cancers and breast cancer cell lines. Importantly, elevated LTBP1 levels appear in two gene signatures predictive of enhanced metastatic behavior. LTBP may promote metastasis by providing the bridge between structural and signaling components of the epithelial to mesenchymal transition (EMT)
PMCID:3747963
PMID: 21494784
ISSN: 1573-7039
CID: 132580

Ltbp1L is focally induced in embryonic mammary mesenchyme, demarcates the ductal luminal lineage and is upregulated during involution

Chandramouli, Anupama; Simundza, Julia; Pinderhughes, Alicia; Hiremath, Minoti; Droguett, Gustavo; Frendewey, David; Cowin, Pamela
INTRODUCTION: Latent TGFbeta binding proteins (LTBPs) govern TGFbeta presentation and activation and are important for elastogenesis. Although TGFbeta is well-known as a tumor suppressor and metastasis promoter, and LTBP1 is elevated in two distinct breast cancer metastasis signatures, LTBPs have not been studied in the normal mammary gland. METHODS: To address this we have examined Ltbp1 promoter activity throughout mammary development using an Ltbp1L-LacZ reporter as well as expression of both Ltbp1L and 1S mRNA and protein by qRT-PCR, immunofluorescence and flow cytometry. RESULTS: Our data show that Ltbp1L is transcribed coincident with lumen formation, providing a rare marker distinguishing ductal from alveolar luminal lineages. Ltbp1L and Ltbp1S are silent during lactation but robustly induced during involution, peaking at the stage when the remodeling process becomes irreversible. Ltbp1L is also induced within the embryonic mammary mesenchyme and maintained within nipple smooth muscle cells and myofibroblasts. Ltbp1 protein exclusively ensheaths ducts and side branches. CONCLUSIONS: These data show Ltbp1 is transcriptionally regulated in a dynamic manner that is likely to impose significant spatial restriction on TGFbeta bioavailability during mammary development. We hypothesize that Ltbp1 functions in a mechanosensory capacity to establish and maintain ductal luminal cell fate, support and detect ductal distension, trigger irreversible involution, and facilitate nipple sphincter function.
PMCID:3978911
PMID: 24262428
ISSN: 1465-5411
CID: 934932

Adhesion g-protein-coupled receptors: elusive hybrids come of age

Simundza, Julia; Cowin, Pamela
Abstract Adhesion G-protein-coupled receptors (GPCRs) are the most recently identified and least understood subfamily of GPCRs. Adhesion GPCRs are characterized by unusually long ectodomains with adhesion-related repeats that facilitate cell- cell and cell-cell matrix contact, as well as a proteolytic cleavage site-containing domain that is a structural hallmark of the family. Their unusual chimeric structure of adhesion-related ectodomain with a seven-pass transmembrane domain and cytoplasmic signaling makes these proteins highly versatile in mediating cellular signaling in response to extracellular adhesion or cell motility events. The ligand binding and cytoplasmic signaling modes for members of this family are beginning to be elucidated, and recent studies have demonstrated critical roles for Adhesion GPCRs in planar polarity and other important cell-cell and cell-matrix interactions during development and morphogenesis, as well as heritable diseases and cancer.
PMCID:4165398
PMID: 24229322
ISSN: 1543-5180
CID: 681042

Breast cancer progression: controversies and consensus in the molecular mechanisms of metastasis and EMT

Cowin, Pamela; Welch, Danny R
PMCID:1963418
PMID: 18769505
ISSN: 1083-3021
CID: 91971

Gli3-mediated repression of Hedgehog targets is required for normal mammary development

Hatsell, Sarah J; Cowin, Pamela
The Hedgehog pathway is vital for the development of many epidermal appendages, but its role in mammary development has been unclear. Here, we show that although Gli2 and Gli3 are expressed during embryonic mammary development, transcriptional reporters of positive Hedgehog signaling are absent. Nevertheless, Gli3(xt/xt) embryos show aberrant early mammary marker expression and lack two pairs of mammary buds, demonstrating that Gli3 is essential for mammary bud formation and preceding patterning events. Misactivation of the Hedgehog pathway by targeted expression of the constitutive activator Gli1, from the Gli2 promoter in Gli3(xt/+) mice, also induces mammary bud loss. Moreover, loss of Gli3 expression induces Gli1 misexpression in mammary mesenchyme. These results establish that the essential function of Gli3 during embryonic mammary development is to repress Hedgehog/Gli1-inducible targets. During postnatal mammary development, Gli2 and Gli3 are expressed in stromal and myoepithelial cells, and Gli3 is also found within the lumenal epithelium. Again, transcriptional reporters of positive Hedgehog signaling are absent from these cell types, yet are expressed robustly within mammary lymphatics. Thus, positive Hedgehog signaling is absent throughout mammary development, distinguishing the mammary gland from other epidermal appendages, such as hair follicles, which require Hedgehog pathway activity
PMID: 16914490
ISSN: 0950-1991
CID: 69584

Untangling desmosomal knots with electron tomography

He, Wanzhong; Cowin, Pamela; Stokes, David L
Cell adhesion by adherens junctions and desmosomes relies on interactions between cadherin molecules. However, the molecular interfaces that define molecular specificity and that mediate adhesion remain controversial. We used electron tomography of plastic sections from neonatal mouse skin to visualize the organization of desmosomes in situ. The resulting three-dimensional maps reveal individual cadherin molecules forming discrete groups and interacting through their tips. Fitting of an x-ray crystal structure for C-cadherin to these maps is consistent with a flexible intermolecular interface mediated by an exchange of amino-terminal tryptophans. This flexibility suggests a novel mechanism for generating both cis and trans interactions and for propagating these adhesive interactions along the junction
PMID: 14526082
ISSN: 1095-9203
CID: 38124

Dissecting the roles of beta-catenin and cyclin D1 during mammary development and neoplasia

Rowlands, Tracey M; Pechenkina, Irina V; Hatsell, Sarah J; Pestell, Richard G; Cowin, Pamela
A considerable body of circumstantial data suggests that cyclin D1 is an attractive candidate to mediate the effects of beta-catenin in mammary tissue. To test the functional significance of these correlative findings, we investigated the genetic interaction between transcriptionally active beta-catenin (DeltaN89beta-catenin) and its target gene cyclin D1 in the mouse mammary gland during pubertal development, pregnancy, and tumorigenesis. Our data demonstrate that cyclin D1 is dispensable for the DeltaN89beta-catenin-stimulated initiation of alveologenesis in virgin females, for the de novo induction of alveoli in males, and for the formation of tumors. Indeed, lack of cyclin D1 accentuates and enhances these hyperplastic and tumorigenic DeltaN89beta-catenin phenotypes. Although alveologenesis is initiated by DeltaN89beta-catenin in a cyclin D1-independent fashion, up-regulation of cyclin D1 occurs in DeltaN89beta-catenin mice and its expression remains essential for the completion of alveolar development during the later stages of pregnancy. Thus, alveologenesis is a two-step process, and cyclin D1 activity during late alveologenesis cannot be replaced by the activity of other beta-catenin target genes that successfully drive proliferation at earlier stages
PMCID:208769
PMID: 13679587
ISSN: 0027-8424
CID: 38126

Plakoglobin: a protein common to different kinds of intercellular adhering junctions

Cowin P; Kapprell HP; Franke WW; Tamkun J; Hynes RO
We have established, by means of a monoclonal antibody and a cDNA clone, that a desmosomal polypeptide of Mr 83,000 also occurs at the plaques of other types of adhering junctions, including the vinculin-actin-associated intercellular junctions, e.g., the zonula adhaerens of epithelial cells and the endothelial, lens, and Sertoli cell junctions. This is the first component found in common among otherwise biochemically distinct plaque domains. Despite its concentration at these intercellular junctions, it is absent from the respective cell-substratum contact sites. In addition, it appears in a globular soluble 7S form in the cytoplasm. We discuss the significance of this protein, for which the name plakoglobin is proposed, in terms of its interaction with such biochemically diverse membrane domains and their different types of associated cytoskeletal filaments
PMID: 3530498
ISSN: 0092-8674
CID: 16341

Delta N89 beta-catenin induces precocious development, differentiation, and neoplasia in mammary gland

Imbert A; Eelkema R; Jordan S; Feiner H; Cowin P
To investigate the role of beta-catenin in mammary gland development and neoplasia, we expressed a stabilized, transcriptionally active form of beta-catenin lacking the NH(2)-terminal 89 amino acids (Delta N 89 beta-catenin) under the control of the mouse mammary tumor virus long terminal repeat. Our results show that Delta N 89 beta-catenin induces precocious lobuloalveolar development and differentiation in the mammary glands of both male and female mice. Virgin Delta N 89 beta-catenin mammary glands resemble those found in wild-type (wt) pregnant mice and inappropriately express cyclin D1 mRNA. In contrast to wt mammary glands, which resume a virgin appearance after cessation of lactation, transgenic mammary glands involute to a midpregnant status. All transgenic females develop multiple aggressive adenocarcinomas early in life. Surprisingly, the Delta N89 beta-catenin phenotype differs from those elicited by overexpression of Wnt genes in this gland. In particular, Delta N 89 beta-catenin has no effect on ductal side branching. This suggests that Wnt induction of ductal branching involves additional downstream effectors or modulators
PMCID:2190562
PMID: 11331306
ISSN: 0021-9525
CID: 20693