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La Crosse, WI, United States

Fu Q.,Gundersen Medical Foundation | Cash S.E.,Gundersen Medical Foundation | Andersen J.J.,Gundersen Medical Center | Kennedy C.R.,Gundersen Medical Foundation | And 6 more authors.
British Journal of Cancer | Year: 2014

Background:Sialophorin is a transmembrane sialoglycoprotein. Normally, the molecule is only produced by white blood cells where it regulates functions such as intercellular adhesion, intracellular signalling, apoptosis, migration and proliferation.Methods:Normal breast tissue and primary breast tumours were analysed by immunohistochemistry for sialophorin expression. The sialophorin-positive breast cancer cell line MCF7 was engineered to stably express either non-targeted or sialophorin-targeted small interfering RNA (siRNA). Assays were then performed in vitro to assess apoptosis, intracellular adhesion, transendothelial migration and cytotoxicity. An orthotopic mouse model assayed ability to produce tumours in vivo.Results:Normal breast epithelial cells exhibit expression of the N-terminal domain of sialophorin in the cytoplasm but not the nucleus. The majority of these normal cells are also negative for expression of the C-terminal domain. In contrast, malignant breast epithelial cells exhibit N-terminal expression both in the cytoplasm and nucleus and the majority express the C-terminus in the nucleus. Using differential patterns of intracellular expression of the N and C termini of sialophorin, we define six subtypes of breast cancer that are independent of histological and receptor status classification. Targeting sialophorin with siRNA resulted in the MCF7 breast cancer cell line exhibiting increased homotypic adhesion, decreased transendothelial migration, increased susceptibility to apoptosis, increased vulnerability to lysis by natural killer cells and decreased ability to produce tumours in mice.Conclusion:Our results indicate that intracellular patterns of sialophorin expression define a new molecular classification of breast cancer and that sialophorin represents a novel therapeutic target. © 2014 Cancer Research UK. Source

Fu Q.,Kabara Cancer Research Institute | Colgan S.P.,Aurora University | Shelley C.S.,University of Wisconsin - Madison | Shelley C.S.,Leukemia Therapeutics LLC
Clinical Medicine and Research | Year: 2016

In the United States the prevalence of end-stage renal disease (ESRD) reached epidemic proportions in 2012 with over 600,000 patients being treated. The rates of ESRD among the elderly are disproportionally high. Consequently, as life expectancy increases and the baby-boom generation reaches retirement age, the already heavy burden imposed by ESRD on the US health care system is set to increase dramatically. ESRD represents the terminal stage of chronic kidney disease (CKD). A large body of evidence indicating that CKD is driven by renal tissue hypoxia has led to the development of therapeutic strategies that increase kidney oxygenation and the contention that chronic hypoxia is the final common pathway to end-stage renal failure. Numerous studies have demonstrated that one of the most potent means by which hypoxic conditions within the kidney produce CKD is by inducing a sustained inflammatory attack by infiltrating leukocytes. Indispensable to this attack is the acquisition by leukocytes of an adhesive phenotype. It was thought that this process resulted exclusively from leukocytes responding to cytokines released from ischemic renal endothelium. However, recently it has been demonstrated that leukocytes also become activated independent of the hypoxic response of endothelial cells. It was found that this endothelium-independent mechanism involves leukocytes directly sensing hypoxia and responding by transcriptional induction of the genes that encode the β2-integrin family of adhesion molecules. This induction likely maintains the long-term inflammation by which hypoxia drives the pathogenesis of CKD. Consequently, targeting these transcriptional mechanisms would appear to represent a promising new therapeutic strategy. © 2016 Marshfield Clinic Health System. Source

Fu Q.,Gundersen Medical Foundation | Cash S.E.,Gundersen Medical Foundation | Andersen J.J.,Gundersen Medical Center | Kennedy C.R.,Gundersen Medical Foundation | And 7 more authors.
International Journal of Cancer | Year: 2013

CD43 is a transmembrane sialoglycoprotein. Normally the molecule is only produced by white blood cells where it regulates functions such as intercellular adhesion, intracellular signaling, apoptosis, migration and proliferation. Two CD43 antibodies were used to interrogate 66 cases of non-small cell lung cancer (NSCLC) and 24 cases of small cell lung cancer (SCLC). In addition, we engineered the CD43-positive lung cancer cell line A549 to stably express either non-targeted or CD43-targeted small-interfering RNA (siRNA). These lines were then subjected to in vitro assays of apoptosis, natural killer (NK) cell cytotoxicity, intercellular adhesion and transendothelial migration. A xenograft mouse model evaluated the ability of the lines to grow primary tumors in vivo. CD43 was found to be expressed in the majority of both SCLC and NSCLC. Inclusive of CD43-negative tumors, differential patterns of nuclear and cytoplasmic expression of CD43 define four molecular subcategories of lung cancer. Targeting CD43 in A549 lung cancer cells, increased homotypic adhesion, decreased heterotypic adhesion and transendothelial migration, increased susceptibility to apoptosis and increased vulnerability to lysis by NK cells. Furthermore, targeting inhibited the growth of primary tumors in nude mice. What's new? Because the glycoprotein CD43 can have diametrically opposite functions in the same cell, it has been compared to Janus, the Roman god with two faces. Although it is normally expressed only in leukocytes, CD43 has also been found in lung cancer cells. In this study, the authors identified four subcategories of lung cancer based on expression patterns of CD43, thus providing a new molecular classification system. In addition, data from RNA interference experiments suggest that CD43 may be a valuable therapeutic target in lung cancer. Copyright © 2012 UICC. Source

Azimi I.,University of Queensland | Beilby H.,University of Queensland | Davis F.M.,University of Queensland | Davis F.M.,University of Cambridge | And 7 more authors.
Molecular Oncology | Year: 2016

Hypoxia is a feature of the microenvironment of many cancers and can trigger epithelial-mesenchymal transition (EMT), a process by which cells acquire a more invasive phenotype with enriched survival. A remodeling of adenosine 5'-triphosphate (ATP)-induced Ca2+ signaling via purinergic receptors is associated with epidermal growth factor (EGF)-induced EMT in MDA-MB-468 breast cancer cells. Here, we assessed ATP-mediated Ca2+ signaling in a model of hypoxia-induced EMT in MDA-MB-468 cells. Like EGF, hypoxia treatment (1% O2) was also associated with a significant reduction in the sensitivity of MDA-MB-468 cells to ATP (EC50 of 0.5 μM for normoxic cells versus EC50 of 5.8 μM for hypoxic cells). Assessment of mRNA levels of a panel of P2X and P2Y purinergic receptors following hypoxia revealed a change in levels of a suite of purinergic receptors. P2X4, P2X5, P2X7, P2Y1 and P2Y11 mRNAs decreased with hypoxia, whereas P2Y6 mRNA increased. Up-regulation of P2Y6 was a common feature of both growth factor- and hypoxia-induced models of EMT. P2Y6 levels were also significantly increased in basal-like breast tumors compared to other subtypes and breast cancer patients with higher P2Y6 levels showed reduced overall survival rates. P2Y6 siRNA-mediated silencing and the P2Y6 pharmacological inhibitor MRS2578 reduced hypoxia-induced vimentin protein expression in MDA-MB-468 cells. P2Y6 inhibition also reduced the migration of mesenchymal-like MDA-MB-231 breast cancer cells. The up-regulation of P2Y6 appears to be a common feature of the mesenchymal phenotype of breast cancer cells and inhibition of this receptor may represent a novel therapeutic target in breast cancer metastasis. © 2015 Federation of European Biochemical Societies. Source

Peterson E.A.,Yeshiva University | Jenkins E.C.,Yeshiva University | Lofgren K.A.,Yeshiva University | Lofgren K.A.,Kabara Cancer Research Institute | And 6 more authors.
Cancer Research | Year: 2015

Estrogen stimulation promotes epithelial cell proliferation in estrogen receptor (ERα)-positive breast cancer. Many ERα target genes have been enumerated, but the identities of the key effectors mediating the estrogen signal remain obscure. During mouse mammary gland development, the estrogen growth factor receptor (EGFR) ligand amphiregulin acts as an important stage-specific effector of estrogen signaling. In this study, we investigated the role of amphiregulin in breast cancer cell proliferation using human tissue samples and tumor xenografts in mice. Amphiregulin was enriched in ERα-positivehumanbreast tumor cells and required for estrogen-dependent growth of MCF7 tumor xenografts. Furthermore, amphiregulin levels were suppressed in patients treated with endocrine therapy. Suppression of EGF receptor signaling appeared necessary for the therapeutic response in this setting. Our findings implicate amphiregulin as a critical mediator of the estrogen response in ERα-positive breast cancer, emphasizing the importance of EGF receptor signaling in breast tumor pathogenesis and therapeutic response. © 2015 American Association for Cancer Research. Source

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