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Effects of Aging on ACTH-Stimulated Steroidogenesis in Subcellular Fractions from Rat Adrenal Glands

Description: Young, middle-aged and old rat adrenal gland steroidogenesis was measured in isolated, superfused glands and in their subcellular fractions before and after adrenocorticotropic hormone treatment. In the latter experiment, five corticosteroids were extracted from six different subcellular fractions. Superfused glands initially produced relatively high glucocorticoid levels; thereafter, production decayed asymptotically. Steroidogenesis by young and middle-aged glands was maintained at least 1.5 to 2.5 hours before it decayed; old glands were 50% less active than younger ones and production decayed within one hour. High cholesterol and progesterone levels in certain old gland fractions were associated with correspondingly reduced 11-deoxycorticosterone and corticosterone. It is suggested that synthesis of these glucocorticoids from their accumulating precursors weakens with age.
Date: August 1982
Creator: Sawada, Tadao
Partner: UNT Libraries

Extracellular matrix control of mammary gland morphogenesis and tumorigenesis: insights from imaging

Description: The extracellular matrix (ECM), once thought to solely provide physical support to a tissue, is a key component of a cell's microenvironment responsible for directing cell fate and maintaining tissue specificity. It stands to reason, then, that changes in the ECM itself or in how signals from the ECM are presented to or interpreted by cells can disrupt tissue organization; the latter is a necessary step for malignant progression. In this review, we elaborate on this concept using the mammary gland as an example. We describe how the ECM directs mammary gland formation and function, and discuss how a cell's inability to interpret these signals - whether as a result of genetic insults or physicochemical alterations in the ECM - disorganizes the gland and promotes malignancy. By restoring context and forcing cells to properly interpret these native signals, aberrant behavior can be quelled and organization re-established. Traditional imaging approaches have been a key complement to the standard biochemical, molecular, and cell biology approaches used in these studies. Utilizing imaging modalities with enhanced spatial resolution in live tissues may uncover additional means by which the ECM regulates tissue structure, on different length scales, through its pericellular organization (short-scale) and by biasing morphogenic and morphostatic gradients (long-scale).
Date: October 23, 2008
Creator: Ghajar, Cyrus M & Bissell, Mina J
Partner: UNT Libraries Government Documents Department

Aging Impacts Transcriptome but not Genome of Hormone-dependentBreast Cancers

Description: Age is one of the most important risk factors for human malignancies, including breast cancer; in addition, age-at-diagnosis has been shown to be an independent indicator of breast cancer prognosis. However, except for inherited forms of breast cancer, there is little genetic or epigenetic understanding of the biological basis linking aging with sporadic breast cancer incidence and its clinical behavior.
Date: October 9, 2007
Creator: Yau, Christina; Fedele, Vita; Roydasgupta, Ritu; Fridlyand, Jane; Hubbard, Alan; Gray, Joe W. et al.
Partner: UNT Libraries Government Documents Department

Apical polarity in three-dimensional culture systems: where to now?

Description: Delineation of the mechanisms that establish and maintain the polarity of epithelial tissues is essential to understanding morphogenesis, tissue specificity and cancer. Three-dimensional culture assays provide a useful platform for dissecting these processes but, as discussed in a recent study in BMC Biology on the culture of mammary gland epithelial cells, multiple parameters that influence the model must be taken into account.
Date: January 21, 2010
Creator: Inman, J. L. & Bissell, Mina
Partner: UNT Libraries Government Documents Department

Normal and tumor-derived myoepithelial cells differ in their ability to interact with luminal breast epithelial cells for polarity and basement membrane deposition

Description: The signals that determine the correct polarity of breast epithelial structures in vivo are not understood. We have shown previously that luminal epithelial cells can be polarized when cultured within a reconstituted basement membrane gel. We reasoned that such cues in vivo may be given by myoepithelial cells. Accordingly, we used an assay where luminal epithelial cells are incorrectly polarized to test this hypothesis. We show that culturing human primary luminal epithelial cells within collagen-I gels leads to formation of structures with no lumina and with reverse polarity as judged by dual stainings for sialomucin, epithelial specific antigen or occludin. No basement membrane is deposited, and {beta}4-integrin staining is negative. Addition of purified human myoepithelial cells isolated from normal glands corrects the inverse polarity, and leads to formation of double-layered acini with central lumina. Among the laminins present in the human breast basement membrane (laminin-1, -5 and -10/11), laminin-1 was unique in its ability to substitute for myoepithelial cells in polarity reversal. Myoepithelial cells were purified also from four different breast cancer sources including a biphasic cell line. Three out of four samples either totally lacked the ability to interact with luminal epithelial cells, or conveyed only correction of polarity in a fraction of acini. This behavior was directly related to the ability of the tumor myoepithelial cells to produce {alpha}-1 chain of laminin. In vivo, breast carcinomas were either negative for laminin-1 (7/12 biopsies) or showed a focal, fragmented deposition of a less intensely stained basement membrane (5/12 biopsies). Dual staining with myoepithelial markers revealed that tumorassociated myoepithelial cells were either negative or weakly positive for expression of laminin-1, establishing a strong correlation between loss of laminin-1 and breast cancer. We conclude that the double-layered breast acinus may be recapitulated in culture and that one reason for the ability ...
Date: October 4, 2001
Creator: Gudjonsson, Thorarinn; Ronnov-Jessen, Lone; Villadsen, Rene; Rank, Fritz; Bissell, Mina J. & Petersen, Ole William
Partner: UNT Libraries Government Documents Department

Identification and targeting of a TACE-dependent autocrine loopwhich predicts poor prognosis in breast cancer

Description: The ability to proliferate independently of signals from other cell types is a fundamental characteristic of tumor cells. Using a 3D culture model of human breast cancer progression, we have delineated a protease-dependent autocrine loop which provides an oncogenic stimulus in the absence of proto-oncogene mutation. Inhibition of this protease, TACE/ADAM17, reverts the malignant phenotype by preventing mobilization of two crucial growth factors, Amphiregulin and TGF{alpha}. We show further that the efficacy of EGFR inhibitors is overcome by physiological levels of growth factors and that successful EGFR inhibition is dependent on reducing ligand bioavailability. Using existing patient outcome data, we demonstrate a strong correlation between TACE and TGF{alpha} expression in human breast cancers that is predictive of poor prognosis.
Date: June 15, 2005
Creator: Kenny, Paraic A. & Bissell, Mina J.
Partner: UNT Libraries Government Documents Department

Of extracellular matrix, scaffolds, and signaling: Tissuearchitectureregulates development, homeostasis, and cancer

Description: The microenvironment surrounding cells influences gene expression, such that a cell's behavior is largely determined by its interactions with the extracellular matrix, neighboring cells, and soluble cues released locally or by distant tissues. We describe the essential role of context and organ structure in directing mammary gland development and differentiated function, and in determining response to oncogenic insults including mutations. We expand on the concept of 'dynamic reciprocity' to present an integrated view of development, cancer, and aging, and posit that genes are like piano keys: while essential, it is the context that makes the music.
Date: March 9, 2006
Creator: Nelson, Celeste M. & Bissell, Mina J.
Partner: UNT Libraries Government Documents Department

Dystroglycan loss disrupts polarity and beta-casein induction inmammary epithelial cells by perturbing laminin anchoring

Description: Precise contact between epithelial cells and their underlying basement membrane is critical to the maintenance of tissue architecture and function. To understand the role that the laminin receptor dystroglycan (DG) plays in these processes, we assayed cell responses to laminin-111 following conditional ablation of DG expression in cultured mammary epithelial cells (MECs). Strikingly, DG loss disrupted laminin-111-induced polarity and {beta}-casein production, and abolished laminin assembly at the step of laminin binding to the cell surface. DG re-expression restored these deficiencies. Investigations of mechanism revealed that DG cytoplasmic sequences were not necessary for laminin assembly and signaling, and only when the entire mucin domain of extracellular DG was deleted did laminin assembly not occur. These results demonstrate that DG is essential as a laminin-111 co-receptor in MECs that functions by mediating laminin anchoring to the cell surface, a process that allows laminin polymerization, tissue polarity, and {beta}-casein induction. The observed loss of laminin-111 assembly and signaling in DG-/-MECs provides insights into the signaling changes occurring in breast carcinomas and other cancers, where DG's laminin-binding function is frequently defective.
Date: February 17, 2006
Creator: Weir, M. Lynn; Oppizzi, Maria Luisa; Henry, Michael D.; Onishi,Akiko; Campbell, Kevin P.; Bissell, Mina J. et al.
Partner: UNT Libraries Government Documents Department

Using Data Fusion to Characterize Breast Tissue

Description: New ultrasound data, obtained with a circular experimental scanner, are compared with data obtained with standard X-ray CT. Ultrasound data obtained by scanning fixed breast tissue were used to generate images of sound speed and reflectivity. The ultrasound images exhibit approximately 1 mm resolution and about 20 dB of dynamic range. All data were obtained in a circular geometry. X-ray CT scans were used to generate X-ray images corresponding to the same 'slices' obtained with the ultrasound scanner. The good match of sensitivity, resolution and angular coverage between the ultrasound and X-ray data makes possible a direct comparison of the three types of images. We present the results of such a comparison for an excised breast fixed in formalin. The results are presented visually using various types of data fusion. A general correspondence between the sound speed, reflectivity and X-ray morphologies is found. The degree to which data fusion can help characterize tissue is assessed by examining the quantitative correlations between the ultrasound and X-ray images.
Date: January 23, 2002
Creator: Littrup, P; Duric, N; Leach, R R; Azevedo, S G; Candy, J V; Moore, T et al.
Partner: UNT Libraries Government Documents Department

Gene Expression in the Third Dimension: The ECM-nucleus Connection

Description: Decades ago, we and others proposed that the dynamic interplay between a cell and its surrounding environment dictates cell phenotype and tissue structure. Whereas much has been discovered about the effects of extracellular matrix molecules on cell growth and tissue specific gene expression, the nuclear mechanisms through which these molecules promote these physiological events remain unknown. Using mammary epithelial cells as a model, the purpose of this review is to discuss how the extracellular matrix influences nuclear structure and function in a three-dimensional context to promote epithelial morphogenesis and function in the mammary gland.
Date: October 1, 2009
Creator: Spencer, Virginia A; Xu, Ren & Bissell, Mina
Partner: UNT Libraries Government Documents Department

Involvement of extracellular matrix constituents in breast cancer

Description: It has recently been established that the extracellular matrix is required for normal functional differentiation of mammary epithelia not only in culture, but also in vivo. The mechanisms by which extracellular matrix affects differentiation, as well as the nature of extracellular matrix constituents which have major impacts on mammary gland function, have only now begun to be dissected. The intricate variety of extracellular matrix-mediated events and the remarkable degree of plasticity of extracellular matrix structure and composition at virtually all times during ontogeny, make such studies difficult. Similarly, during carcinogenesis, the extracellular matrix undergoes gross alterations, the consequences of which are not yet precisely understood. Nevertheless, an increasing amount of data suggests that the extracellular matrix and extracellular matrix-receptors might participate in the control of most, if not all, of the successive stages of breast tumors, from appearance to progression and metastasis.
Date: June 1, 1995
Creator: Lochter, Andre & Bissell, Mina J
Partner: UNT Libraries Government Documents Department

A hierarchy of ECM-mediated signalling tissue-specific gene expression regulates tissue-specific gene expression

Description: A dynamic and reciprocal flow of information between cells and the extracellular matrix contributes significantly to the regulation of form and function in developing systems. Signals generated by the extracellular matrix do not act in isolation. Instead, they are processed within the context of global signalling hierarchies whose constituent inputs and outputs are constantly modulated by all the factors present in the cell's surrounding microenvironment. This is particularly evident in the mammary gland, where the construction and subsequent destruction of such a hierarchy regulates changes in tissue-specific gene expression, morphogenesis and apoptosis during each developmental cycle of pregnancy, lactation and involution.
Date: October 7, 1995
Creator: Roskelley, Calvin D; Srebrow, Anabella & Bissell, Mina J
Partner: UNT Libraries Government Documents Department

The plasticity of human breast carcinoma cells is more than epithelial to mesenchymal conversion

Description: The human breast comprises three lineages: the luminal epithelial lineage, the myoepithelial lineage, and the mesenchymal lineage. It has been widely accepted that human breast neoplasia pertains only to the luminal epithelial lineage. In recent years, however, evidence has accumulated that neoplastic breast epithelial cells may be substantially more plastic in their differentiation repertoire than previously anticipated. Thus, along with an increasing availability of markers for the myoepithelial lineage, at least a partial differentiation towards this lineage is being revealed frequently. It has also become clear that conversions towards the mesenchymal lineage actually occur, referred to as epithelial to mesenchymal transitions. Indeed, some of the so-called myofibroblasts surrounding the tumor may indeed have an epithelial origin rather than a mesenchymal origin. Because myoepithelial cells, epithelial to mesenchymal transition-derived cells, genuine stromal cells and myofibroblasts share common markers, we now need to define a more ambitious set of markers to distinguish these cell types in the microenvironment of the tumors. This is necessary because the different microenvironments may confer different clinical outcomes. The aim of this commentary is to describe some of the inherent complexities in defining cellular phenotypes in the microenvironment of breast cancer and to expand wherever possible on the implications for tumor suppression and progression.
Date: May 12, 2001
Creator: Petersen, Ole William; Nielsen, Helga Lind; Gudjonsson, Thorarinn; Villadsen, René Ronnov-Jessen, Lone & Bissell, Mina J.
Partner: UNT Libraries Government Documents Department

Polo-like Kinase I is involved in Invasion through Extracellular Matrix

Description: Polo-like kinase 1, PLK1, has important functions in maintaining genome stability and is involved in regulation of mitosis. PLK1 is up regulated in many invasive carcinomas. We asked whether it may also play a role in acquisition of invasiveness, a crucial step in transition to malignancy. In a model of metaplastic basal-like breast carcinoma progression, we found that PLK1 expression is necessary but not sufficient to induce invasiveness through laminin-rich extracellular matrix. PLK1 mediates invasion via Vimentin and {beta}1 integrin, both of which are necessary. We observed that PLK1 phosphorylates Vimentin on serine 82, which in turn regulates cell surface levels of {beta}1 integrin. We found PLK1 to be also highly expressed in pre-invasive in situ carcinomas of the breast. These results support a role for the involvement of PLK1 in the invasion process and point to this pathway as a potential therapeutic target for pre-invasive and invasive breast carcinoma treatment.
Date: April 2, 2008
Creator: Bissell, Mina J; Rizki, Aylin; Mott, Joni D. & Bissell, Mina J
Partner: UNT Libraries Government Documents Department

MCF-10A-NeoST: A New Cell System for Studying Cell-ECM and Cell-Cell Interactions in Breast Cancer

Description: There is a continuing need for genetically matched cell systems to model cellular behaviors that are frequently observed in aggressive breast cancers. We report here the isolation and initial characterization of a spontaneously arising variant of MCF-10A cells, NeoST, which provides a new model to study cell adhesion and signal transduction in breast cancer. NeoST cells recapitulate important biological and biochemical features of metastatic breast cancer, including anchorage-independent growth, invasiveness in threedimensional reconstituted membranes, loss of E-cadherin expression, and increased tyrosine kinase activity. A comprehensive analysis of tyrosine kinase expression revealed overexpression or functional activation of the Axl, FAK, and EphA2 tyrosine kinases in transformed MCF-10A cells. MCF-10A and these new derivatives provide a genetically matched model to study defects in cell adhesion and signaling that are relevant to cellular behaviors that often typify aggressive breast cancer cells.
Date: August 22, 2001
Creator: Zantek, Nicole Dodge; Walker-Daniels, Jennifer; Stewart, Jane; Hansen, Rhonda K.; Robinson, Daniel; Miao, Hui et al.
Partner: UNT Libraries Government Documents Department

Of Microenvironments and Mammary Stem Cells

Description: In most adult tissues there reside pools of stem and progenitor cells inside specialized microenvironments referred to as niches. The niche protects the stem cells from inappropriate expansion and directs their critical functions. Thus guided, stem cells are able to maintain tissue homeostasis throughout the ebb and flow of metabolic and physical demands encountered over a lifetime. Indeed, a pool of stem cells maintains mammary gland structure throughout development, and responds to the physiological demands associated with pregnancy. This review discusses how stem cells were identified in both human and mouse mammary glands; each requiring different techniques that were determined by differing biological needs and ethical constraints. These studies together create a robust portrait of mammary gland biology and identify the location of the stem cell niche, elucidate a developmental hierarchy, and suggest how the niche might be manipulated for therapeutic benefit.
Date: June 1, 2007
Creator: LaBarge, Mark A; Petersen, Ole W & Bissell, Mina J
Partner: UNT Libraries Government Documents Department

Targeted Expression of Stromelysin-1 in Mammary Gland Provides Evidence for a Role of Proteinases in Branching Morphogenesis and the Requirement for an Intact Basement Membrane for Tissue-specific Gene Expression

Description: The extracellular matrix (ECM) is an important regulator of the differentiated phenotype of mammary epithelial cells in culture. Despite the fact that ECM-degrading enzymes have been implicated in morphogenesis and tissue remodeling, there is little evidence for a direct role for such regulation in vivo. We generated transgenic mice that express autoactivated isoforms of the matrix metalloproteinase stromelysin-1, under the control of the whey acidic protein gene promoter, to examine the effect of inappropriate expression of this enzyme. Stromelysin-1 is implicated as the primary player in the loss of basement membrane and loss of function in the mammary gland during involution. The transgene was expressed at low levels in mammary glands of virgin female mice, leading to an unexpected phenotype: The primary ducts had supernumerary branches and showed precocious development of alveoli that expressed beta-casein at levels similar to that of an early- to mid-pregnant gland. Lactating glands showed high levels of transgene expression, with accumulation at the basement membrane, and a decrease in laminin and collagen IV, resulting in a loss of basement membrane integrity; this was accompanied by a dramatic alteration of alveolar morphology, with decreased size and shrunken lumina containing little beta-casein. During pregnancy, expression of endogenous whey acidic protein and beta-casein was reduced in transgenic glands, confirming the observed dependence of milk protein transcription of ECM in mammary epithelial cells in culture. These data provide direct evidence that stromelysin-1 activity can be morphogenic for mammary epithelial cells, inducing hyperproliferation and differentiation in virgin animals, and that its lytic activity can, indeed, disrupt membrane integrity and reduce mammary-specific function. We conclude that the balance of ECM-degrading enzymes with their inhibitors, and the associated regulation of ECM structure, is crucial for tissue-specific gene expression and morphogenesis in vivo.
Date: May 1, 1994
Creator: Sympson, Carolyn J; Talhouk, Rabih S; Alexander, Caroline M; Chin, Jennie R; Cliff, Shirley M; Bissell, Mina J et al.
Partner: UNT Libraries Government Documents Department

Two distinct phases of apoptosis in mammary gland involution: proteinase-independent and -dependent pathways

Description: Postlactational involution of the mammary gland is characterized by two distinct physiological events: apoptosis of the secretory, epithelial cells undergoing programmed cell death, and proteolytic degradation of the mammary gland basement membrane. We examined the spatial and temporal patterns of apoptotic cells in relation to those of proteinases during involution of the BALB/c mouse mammary gland. Apoptosis was almost absent during lactation but became evident at day 2 of involution, when {beta}-casein gene expression was still high. Apoptotic cells were then seen at least up to day 8 of involution, when {beta}-casein gene expression was being extinguished. Expression of sulfated glycoprotein-2 (SGP-2), interleukin-1{beta} converting enzyme (ICE) and tissue inhibitor of metalloproteinases-1 was upregulated at day 2, when apoptotic cells were seen initially. Expression of the matrix metalloproteinases gelatinase A and stromelysin-1 and the serine proteinase urokinase-type plasminogen activator, which was low during lactation, was strongly upregulated in parallel starting at day 4 after weaning, coinciding with start of the collapse of the lobulo-alveolar structures and the intensive tissue remodeling in involution. The major sites of mRNA synthesis for these proteinases were fibroblast-like cells in the periductal stroma and stromal cells surrounding the collapsed alveoli, suggesting that the degradative phase of involution is due to a specialized mesenchymal-epithelial interaction. To elucidate the functional role of these proteinases during involution, at the onset of weaning we treated mice systemically with the glucocorticoid hydrocortisone, which is known to inhibit mammary gland involution. Although the initial wave of apoptotic cells appeared in the lumina of the gland, the dramatic regression and tissue remodeling usually evident by day 5 was substantially inhibited by systemic treatment with hydrocortisone. mRNA and protein for gelatinase A, stromelysin-1 and uPA were weakly induced, if at all, in hydrocortisonetreated mice. Furthermore, mRNA for membrane-type matrix metalloproteinase decreased after hydrocortisone treatment ...
Date: January 1, 1996
Creator: Lund, Leif R; Romer, John; Thomasset, Nicole; Solberg, Helene; Pyke, Charles; Bissell, Mina J et al.
Partner: UNT Libraries Government Documents Department

Expression of Autoactivated Stromelysin-1 in Mammary Glands of Transgenic Mice Leads to a Reactive Stroma During Early Development

Description: Extracellular matrix and extracellular matrix-degrading matrix metalloproteinases play a key role in interactions between the epithelium and the mesenchyme during mammary gland development and disease. In patients with breast cancer, the mammary mesenchyme undergoes a stromal reaction, the etiology of which is unknown. We previously showed that targeting of an autoactivating mutant of the matrix metalloproteinase stromelysin-1 to mammary epithelia of transgenic mice resulted in reduced mammary function during pregnancy and development of preneoplastic and neoplastic lesions. Here we examine the cascade of alterations before breast tumor formation in the mammary gland stroma once the expression of the stromelysin-1 transgene commences. Beginning in postpubertal virgin animals, low levels of transgene expression in mammary epithelia led to increased expression of endogenous stromelysin-1 in stromal fibroblasts and up-regulation of other matrix metalloproteinases, without basement membrane disruption. These changes were accompanied by the progressive development of a compensatory reactive stroma, characterized by increased collagen content and vascularization in glands from virgin mice. This remodeling of the gland affected epithelial-mesenchymal communication as indicated by inappropriate expression of tenascin-C starting by day 6 of pregnancy. This, together with increased transgene expression, led to basement membrane disruption starting by day 15 of pregnancy. We propose that the highly reactive stroma provides a prelude to breast epithelial tumors observed in these animals. Epithelial development depends on an exquisite series of inductive and instructive interactions between the differentiating epithelium and the mesenchymal (stromal) compartment. The epithelium, which consists of luminal and myoepithelial cells, is separated from the stroma by a basement membrane (BM), which plays a central role in mammary gland homeostasis and gene expression. In vivo, stromal cells produce fibronectin, collagens, proteoglycans, and some components of the BM, as well as a number of proteinases that can effectively degrade BM constituents. Stromal and epithelial cells of the ...
Date: April 24, 1998
Creator: Thomasset, N.; Lochter, A.; Sympson, C.J.; Lund, L.R.; Williams, D.R.; Behrendtsen, O. et al.
Partner: UNT Libraries Government Documents Department