Mammary tumors initiated by constitutive Cdk2 activation contain an invasive basal-like component.

Corsino PE, Davis BJ, Nørgaard PH, Parker NN, Law M, Dunn W, Law BK
Neoplasia. 2008 10 (11): 1240-52

PMID: 18953433 · PMCID: PMC2570600 · DOI:10.1593/neo.08710

The basal-like subtype of breast cancer is associated with invasiveness, high rates of postsurgical recurrence, and poor prognosis. Aside from inactivation of the BRCA1 tumor-suppressor gene, little is known concerning the mechanisms that cause basal breast cancer or the mechanisms responsible for its invasiveness. Here, we show that the heterogeneous mouse mammary tumor virus-cyclin D1-Cdk2 (MMTV-D1K2) transgenic mouse mammary tumors contain regions of spindle-shaped cells expressing both luminal and myoepithelial markers. Cell lines cultured from these tumors exhibit the same luminal/myoepithelial mixed-lineage phenotype that is associated with human basal-like breast cancer and express a number of myoepithelial markers including cytokeratin 14, P-cadherin, alpha smooth muscle actin, and nestin. The MMTV-D1K2 tumor-derived cell lines form highly invasive tumors when injected into mouse mammary glands. Invasion is associated with E-cadherin localization to the cytoplasm or loss of E-cadherin expression. Cytoplasmic E-cadherin correlates with lack of colony formation in vitro and beta-catenin and p120(ctn) localization to the cytoplasm. The data suggest that the invasiveness of these cell lines results from a combination of factors including mislocalization of E-cadherin, beta-catenin, and p120(ctn) to the cytoplasm. Nestin expression and E-cadherin mislocalization were also observed in human basal-like breast cancer cell lines, suggesting that these results are relevant to human tumors. Together, these results suggest that abnormal Cdk2 activation may contribute to the formation of basal-like breast cancers.

MeSH Terms (27)

Animals beta Catenin Breast Neoplasms Cadherins Catenins Cell Adhesion Molecules Cell Line, Tumor Cyclin-Dependent Kinase 2 Cyclin D1 Female Humans Immunoblotting Immunohistochemistry Intermediate Filament Proteins Mammary Neoplasms, Experimental Mammary Tumor Virus, Mouse Metalloproteins Mice Mice, Transgenic Microscopy, Fluorescence Neoplasm Invasiveness Nerve Tissue Proteins Nestin Phosphoproteins Protein Transport Stress Fibers Zyxin

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