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Richland Center, 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.,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

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