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

Autor: Fu Q; Department of Cancer Research, Gundersen Medical Foundation, La Crosse, WI 54601, USA., Cash SE; Department of Cancer Research, Gundersen Medical Foundation, La Crosse, WI 54601, USA., Andersen JJ; Department of Pathology, Gundersen Medical Center, La Crosse, WI 54601, USA., Kennedy CR; Department of Cancer Research, Gundersen Medical Foundation, La Crosse, WI 54601, USA., Madadi AR; Department of Medical Oncology, Gundersen Medical Center, La Crosse, WI 54601, USA., Raghavendra M; Department of Medical Oncology, Gundersen Medical Center, La Crosse, WI 54601, USA., Dietrich LL; Department of Medical Oncology, Gundersen Medical Center, La Crosse, WI 54601, USA., Agger WA; Department of Infectious Disease, Gundersen Medical Center, La Crosse, WI 54601, USA., Shelley CS; 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.
Jazyk: angličtina
Zdroj: British journal of cancer [Br J Cancer] 2014 Jan 07; Vol. 110 (1), pp. 146-55. Date of Electronic Publication: 2013 Nov 26.
DOI: 10.1038/bjc.2013.526
Abstrakt: 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.
Databáze: MEDLINE
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