Intracellular patterns of sialophorin expression define a new molecular classification of breast cancer and represent new targets for therapy.

Publisher: Nature Publishing Group on behalf of Cancer Research UK Country of Publication: England NLM ID: 0370635 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1532-1827 (Electronic) Linking ISSN: 00070920 NLM ISO Abbreviation: Br J Cancer Subsets: MEDLINE

Publication: 2002- : London : Nature Publishing Group on behalf of Cancer Research UK
Original Publication: London, Lewis.

Breast Neoplasms/*metabolism ; Leukosialin/*biosynthesis; Amino Acid Sequence ; Animals ; Apoptosis/drug effects ; Apoptosis/physiology ; Breast Neoplasms/genetics ; Cell Adhesion/physiology ; Cell Line, Tumor ; Cell Movement/physiology ; Cell Nucleus/metabolism ; Cytoplasm/metabolism ; Female ; Humans ; Immunohistochemistry ; Leukosialin/genetics ; MCF-7 Cells ; Mice ; Mice, Nude ; Molecular Sequence Data ; RNA, Small Interfering/administration & dosage ; RNA, Small Interfering/genetics ; Retrospective Studies ; Tumor Necrosis Factor-alpha/pharmacology

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.

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10ST1051 United States ST OHS HRSA HHS

0 (Leukosialin)
0 (RNA, Small Interfering)
0 (SPN protein, human)
0 (Tumor Necrosis Factor-alpha)

Date Created: 20131128 Date Completed: 20140310 Latest Revision: 20211021

20250114

PMC3887278

10.1038/bjc.2013.526

24281005