title: Intracellular patterns of sialophorin expression define a new molecular classification of breast cancer and represent new targets for therapy.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Cancer Research, Gundersen Medical Foundation, La Crosse, WI 54601, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Fu
authors.affiliation: Department of Cancer Research, Gundersen Medical Foundation, La Crosse, WI 54601, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Cash
authors.affiliation: Department of Pathology, Gundersen Medical Center, La Crosse, WI 54601, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Andersen
authors.affiliation: Department of Cancer Research, Gundersen Medical Foundation, La Crosse, WI 54601, USA.
authors.forename: C R
authors.initials: CR
authors.lastname: Kennedy
authors.affiliation: Department of Medical Oncology, Gundersen Medical Center, La Crosse, WI 54601, USA.
authors.forename: A R
authors.initials: AR
authors.lastname: Madadi
authors.affiliation: Department of Medical Oncology, Gundersen Medical Center, La Crosse, WI 54601, USA.
authors.forename: M
authors.initials: M
authors.lastname: Raghavendra
authors.affiliation: Department of Medical Oncology, Gundersen Medical Center, La Crosse, WI 54601, USA.
authors.forename: L L
authors.initials: LL
authors.lastname: Dietrich
authors.affiliation: Department of Infectious Disease, Gundersen Medical Center, La Crosse, WI 54601, USA.
authors.forename: W A
authors.initials: WA
authors.lastname: Agger
authors.affiliation: 1] Department of Cancer Research, Gundersen Medical Foundation, La Crosse, WI 54601, USA [2] Kabara Cancer Research Institute, Gundersen Medical Foundation, La Crosse, WI 54601, USA.
authors.forename: C S
authors.initials: CS
authors.lastname: Shelley
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051917:Leukosialin / Q000096:biosynthesis* / Q000235:genetics; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D012189:Retrospective Studies; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D051917:Leukosialin; D034741:RNA, Small Interfering; C465014:SPN protein, human; D014409:Tumor Necrosis Factor-alpha