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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

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

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

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

A Combined Scintimammography/Stereotactic Core Biopsy Digital X-ray System

Description: Jefferson Lab, Hampton University and the Riverside Regional Medical Center are collaborating in a clinical study employing a dual modality imaging system utilizing scintimammography and digital radiography. The purpose of the study is to obtain clinical data on the reliability of scintimammography in predicting the malignancy of suspected breast lesions with the ultimate goal to reduce the number of false positives associated with conventional x-ray mammography. The scintimammography gamma camera is a custom built mini gamma camera with an active area of 5.3 cm x 5.3 cm based on a 2x2 array of Hamamatsu R7600-C8 position sensitive photomultiplier tubes. The spatial resolution of the gamma camera at the collimator surface is <4 mm FWHM and the sensitivity is 4000 cps/mCi. Preliminary results are that of the six cases that indicated a lesion with high uptake of MiraLuma ({sup 99m}Tc-sestamibi) five were positive for cancer. Out of a total of 25 patients in the study, all cases negative for MiraLuma uptake were confirmed negative via the biopsy pathology. The scintimammography results indicate that the lesions become visible with the mini gamma camera within 3 minutes post injection of MiraLuma.
Date: October 20, 2000
Creator: Weisenberger, A. G.; Barbosa, F.; Green, T. D.; Hoefer, R.; Keppel, C.; Kross, B. et al.
Partner: UNT Libraries Government Documents Department

Optimization of Dedicated Scintimammography Procedure Using Detector Prototypes and Compressible Phantoms

Description: Results are presented on the optimization of the design and use of dedicated compact scintimammography gamma cameras. Prototype imagers with a field-of-view (FOV) of 5 cm x 5 cm, 10 cm x 10 cm and 15 cm x 20 cm were used in either a dual modality mode as an adjunct technique to digital x-ray mammography imagers or as stand-alone instruments such as dedicated breast SPECT and planar imagers. Experimental data was acquired to select the best imaging modality (SPECT or planar) to detect small lesions using Tc{sup 99m} radio-labeled pharmaceuticals. In addition, studies were preformed to optimize the imaging geometry. Results suggest that the preferred imaging geometry is planar imaging with two opposing detector heads while the breast is under compression, however further study of the dedicated breast SPECT is warranted.
Date: October 1, 2000
Creator: Majewski, S.; Kieper, D.; Curran, E.; Keppel, C.; Kross, B.; Palumbo, A. et al.
Partner: UNT Libraries Government Documents Department

Instrumentation optimization for positron emission mammography

Description: The past several years have seen designs for PET cameras optimized to image the breast, commonly known as Positron Emission Mammography or PEM cameras. The guiding principal behind PEM instrumentation is that a camera whose field of view is restricted to a single breast has higher performance and lower cost than a conventional PET camera. The most common geometry is a pair of parallel planes of detector modules, although geometries that encircle the breast have also been proposed. The ability of the detector modules to measure the depth of interaction (DOI) is also a relevant feature. This paper finds that while both the additional solid angle coverage afforded by encircling the breast and the decreased blurring afforded by the DOI measurement improve performance, the ability to measure DOI is more important than the ability to encircle the breast.
Date: June 5, 2003
Creator: Moses, William W. & Qi, Jinyi
Partner: UNT Libraries Government Documents Department

Cyr61 promotes breast tumorigenesis and cancer progression

Description: Cyr61, a member of the CCN family of genes, is an angiogenic factor. We have shown that it is overexpressed in invasive and metastatic human breast cancer cells and tissues. Here, we investigated whether Cyr61 is necessary and/or sufficient to bypass the ''normal'' estrogen (E2) requirements for breast cancer cell growth. Our results demonstrate that under E2-depleted condition, Cyr61 is sufficient to induce MCF-7 cells grow in the absence of E2. MCF-7 cells transfected with Cyr61 (MCF-7/Cyr61) became E2-independent but still E2-responsive. On the other hand, MCF-7/vector cells remain E2-dependent. MCF-7/Cyr61 cells acquire an antiestrogen-resistant phenotype, one of the most common clinical occurrences during breast cancer progression. MCF-7/Cyr61 cells are anchorage-independent and capable of forming Matrigel outgrowth patterns in the absence of E2. ERa expression in MCF-7/Cyr61 cells is decreased although still functional. Additionally, MCF-7/Cyr61 cells are tumorigenic in ovariectomized athymic nude mice. The tumors resemble human invasive carcinomas with increased vascularization and overexpression of vascular endothelial growth factor (VEGF). Our results demonstrate that Cyr61 is a tumor-promoting factor and a key regulator of breast cancer progression. This study provides evidence that Cyr61 is sufficient to induce E2-independence and anti-E2 resistance, and to promote invasiveness in vitro, and to induce tumorigenesis in vivo, all of which are characteristics of an aggressive breast cancer phenotype.
Date: January 16, 2002
Creator: Tsai, Miaw-Sheue; Bogart, Daphne F.; Castaneda, Jessica M.; Li, Patricia & Lupu, Ruth
Partner: UNT Libraries Government Documents Department

Stromal-epithelial interactions in aging and cancer: Senescent fibroblasts alter epithelial cell differentiation

Description: Cellular senescence suppresses cancer by arresting cells at risk for malignant tumorigenesis. However, senescent cells also secrete molecules that can stimulate premalignant cells to proliferate and form tumors, suggesting the senescence response is antagonistically pleiotropic. We show that premalignant mammary epithelial cells exposed to senescent human fibroblasts in mice irreversibly lose differentiated properties, become invasive and undergo full malignant transformation. Moreover, using cultured mouse or human fibroblasts and non-malignant breast epithelial cells, we show that senescent fibroblasts disrupt epithelial alveolar morphogenesis, functional differentiation, and branching morphogenesis. Further, we identify MMP-3 as the major factor responsible for the effects of senescent fibroblasts on branching morphogenesis. Our findings support the idea that senescent cells contribute to age-related pathology, including cancer, and describe a new property of senescent fibroblasts--the ability to alter epithelial differentiation--that might also explain the loss of tissue function and organization that is a hallmark of aging.
Date: July 14, 2004
Creator: Parrinello, Simona; Coppe, Jean-Philippe; Krtolica, Ana & Campisi, Judith
Partner: UNT Libraries Government Documents Department

Automated analysis for microcalcifications in high resolution digital mammograms

Description: Digital mammography offers the promise of significant advances in early detection of breast cancer. Our overall goal is to design a digital system which improves upon every aspect of current mammography technology: the x-ray source, detector, visual presentation of the mammogram and computer-aided diagnosis capabilities. This paper will discuss one part of our whole-system approach -- the development of a computer algorithm using gray-scale morphology to automatically analyze and flag microcalcifications in digital mammograms in hopes of reducing the current percentage of false-negative diagnoses, which is estimated at 20%. The mamrnograms used for developing this ``mammographers assistant`` are film mammograms which we have digitized at either 70{mu}m or 35{mu}m per pixel resolution with 4096(12 bits) of gray level per pixel. For each potential microcalcification detected. in these images, we compute a number of features in order to distinguish between the different kinds of objects detected.
Date: October 1, 1994
Creator: Mascio, L.N.; Hernandez, J.M. & Logan, C.M.
Partner: UNT Libraries Government Documents Department