The transcription factor ATF3 acts as an oncogene in mouse mammary tumorigenesis

<p>Abstract</p> <p>Background</p> <p>Overexpression of the bZip transcription factor, ATF3, in basal epithelial cells of transgenic mice under the control of the bovine cytokeratin-5 (CK5) promoter has previously been shown to induce epidermal hyperplasia, hair follicle anomalies and neoplastic lesions of the oral mucosa including squamous cell carcinomas. CK5 is known to be expressed in myoepithelial cells of the mammary gland, suggesting the possibility that transgenic BK5.ATF3 mice may exhibit mammary gland phenotypes.</p> <p>Methods</p> <p>Mammary glands from nulliparous mice in our BK5.ATF3 colony, both non-transgenic and transgenic, were examined for anomalies by histopathology and immunohistochemistry. Nulliparous and biparous female mice were observed for possible mammary tumor development, and suspicious masses were analyzed by histopathology and immunohistochemistry. Human breast tumor samples, as well as normal breast tissue, were similarly analyzed for ATF3 expression.</p> <p>Results</p> <p>Transgenic BK5.ATF3 mice expressed nuclear ATF3 in the basal layer of the mammary ductal epithelium, and often developed squamous metaplastic lesions in one or more mammary glands by 25 weeks of age. No progression to malignancy was seen in nulliparous BK5.ATF3 or non-transgenic mice held for 16 months. However, biparous BK5.ATF3 mice developed mammary carcinomas with squamous metaplasia between 6 months and one year of age, reaching an incidence of 67%. Cytokeratin expression in the tumors was profoundly disturbed, including expression of CK5 and CK8 (characteristic of basal and luminal cells, respectively) throughout the epithelial component of the tumors, CK6 (potentially a stem cell marker), CK10 (a marker of interfollicular epidermal differentiation), and mIRSa2 and mIRSa3.1 (markers of the inner root sheath of hair follicles). Immunohistochemical studies indicated that a subset of human breast tumors exhibit high levels of nuclear ATF3 expression.</p> <p>Conclusion</p> <p>Overexpression of ATF3 in CK5-expressing cells of the murine mammary gland results in the development of squamous metaplastic lesions in nulliparous females, and in mammary tumors in biparous mice, suggesting that ATF3 acts as a mammary oncogene. A subset of human breast tumors expresses high levels of ATF3, suggesting that ATF3 may play an oncogenic role in human breast tumorigenesis, and therefore may be useful as either a biomarker or therapeutic target.</p

Activation of the Canonical Wnt/β-Catenin Pathway in ATF3-Induced Mammary Tumors

Female transgenic mice that constitutively overexpress the transcription factor ATF3 in the basal epithelium of the mammary gland develop mammary carcinomas with high frequency, but only if allowed to mate and raise pups early in life. This transgenic mouse model system reproduces some features of human breast cancer in that about 20% of human breast tumor specimens exhibit overexpression of ATF3 in the tumor cells. The ATF3-induced mouse tumors are phenotypically similar to mammary tumors induced by overexpression of activating Wnt/β-catenin pathway genes. We now show that the Wnt/β-catenin pathway is indeed activated in ATF3-induced tumors. β-catenin is transcriptionally up-regulated in the tumors, and high levels of nuclear β-catenin are seen in tumor cells. A reporter gene for Wnt/β-catenin pathway activity, TOPGAL, is up-regulated in the tumors and several downstream targets of Wnt signaling, including Ccnd1, Jun, Axin2 and Dkk4, are also expressed at higher levels in ATF3-induced tumors compared to mammary glands of transgenic females. Several positive-acting ligands for this pathway, including Wnt3, Wnt3a, Wnt7b, and Wnt5a, are significantly overexpressed in tumor tissue, and mRNA for Wnt3 is about 5-fold more abundant in transgenic mammary tissue than in non-transgenic mammary tissue. Two known transcriptional targets of ATF3, Snai1 and Snai2, are also overexpressed in the tumors, and Snail and Slug proteins are found to be located primarily in the nuclei of tumor cells. In vitro knockdown of Atf3 expression results in significant decreases in expression of Wnt7b, Tcf7, Snai2 and Jun, suggesting that these genes may be direct transcriptional targets of ATF3 protein. By chromatin immunoprecipitation analysis, both ATF3 and JUN proteins appear to bind to a particular subclass of AP-1 sites upstream of the transcriptional start sites of each of these genes

Mean flow and turbulence characteristics in whirling annular seals

Due to the character of the original source materials and the nature of batch digitization, quality control issues may be present in this document. Please report any quality issues you encounter to [email protected], referencing the URI of the item.Includes bibliographical references.Not availabl

‘NEW TECHNOLOGY’ DATA RECORDERS A TECHNOLOGY OVERVIEW

International Telemetering Conference Proceedings / October 22-25, 2001 / Riviera Hotel and Convention Center, Las Vegas, NevadaThere are clear signs that data recorders using solid-state and disk-based technologies now represent a serious alternative to conventional linear and rotary tape recorders for a broad spectrum of data capture applications. As the number of RFQs specifying these so-called ‘new technology’ solutions increases, virtually every major manufacturer has responded with announcements of new off-the-shelf products. A NATO technical support team has even been tasked with drafting standards for certain aspects of solid-state and disk recorders. But what has caused this sudden explosion of interest? Strange to say, in almost every case it has been the perceived shortcomings of the new technologies which have forced the issue. For all their advantages, solid-state and disk recorders are essentially only temporary storage devices. To overcome this problem manufacturers have found it necessary to address the total data capture/storage/distribution/archiving scenario – with some interesting results. It is in the ‘data handling’ area therefore that some of the most significant advances are to be found. This Paper offers an overview of some of the new technology solutions now available - RAID (Redundant Arrays of Independent Disks), JBOD (Just a Bunch Of Disks) and FLASH memory recorders. New paradigms for airborne, mobile and laboratory data collection, handling, analysis and archiving are discussed, demonstrating that (for once) the migration path has been carefully thought through, with industry-standard data interfaces, true computer connectivity (Windows and UNIX) and familiar control techniques. It concludes that many users with a keen interest in replacing legacy products for whatever reason can now do so with confidence and minimal disruption to their day-to-day operation while nevertheless gaining access to the important benefits which ‘new technology’ solutions can offer.International Foundation for TelemeteringProceedings from the International Telemetering Conference are made available by the International Foundation for Telemetering and the University of Arizona Libraries. Visit http://www.telemetry.org/index.php/contact-us if you have questions about items in this collection

GREEN FRINGED ORCHID (PLATANTHERA LACERA, ORCHIDACEAE) IN SOUTHERN LOUISIANA

Volume: 22Start Page: 805End Page: 80