Corsino Patrick E, Davis Bradley J, Nørgaard Peter H, Parker Nicole N Teoh, Law Mary, Dunn William, Law Brian K
Department of Pharmacology and Therapeutics, Shands Cancer Center, University of Florida, Gainesville, FL 32610, USA.
Neoplasia. 2008 Nov;10(11):1240-52. 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.
乳腺癌的基底样亚型与侵袭性、术后高复发率及不良预后相关。除了BRCA1肿瘤抑制基因失活外，关于导致基底样乳腺癌的机制或其侵袭性的机制所知甚少。在此，我们表明，异质性小鼠乳腺肿瘤病毒-细胞周期蛋白D1-细胞周期蛋白依赖性激酶2（MMTV-D1K2）转基因小鼠乳腺肿瘤包含表达管腔和肌上皮标志物的纺锤形细胞区域。从这些肿瘤培养的细胞系表现出与人类基底样乳腺癌相关的相同管腔/肌上皮混合谱系表型，并表达多种肌上皮标志物，包括细胞角蛋白14、P-钙黏蛋白、α平滑肌肌动蛋白和巢蛋白。将MMTV-D1K2肿瘤衍生的细胞系注射到小鼠乳腺中时会形成高度侵袭性肿瘤。侵袭与E-钙黏蛋白定位到细胞质或E-钙黏蛋白表达缺失有关。细胞质E-钙黏蛋白与体外集落形成缺乏以及β-连环蛋白和p120（ctn）定位到细胞质相关。数据表明，这些细胞系的侵袭性是由多种因素共同导致的，包括E-钙黏蛋白、β-连环蛋白和p120（ctn）定位到细胞质的错误定位。在人类基底样乳腺癌细胞系中也观察到巢蛋白表达和E-钙黏蛋白定位错误，表明这些结果与人类肿瘤相关。总之，这些结果表明异常的Cdk2激活可能有助于基底样乳腺癌的形成。
