Storci G, Sansone P, Trere D, Tavolari S, Taffurelli M, Ceccarelli C, Guarnieri T, Paterini P, Pariali M, Montanaro L, Santini D, Chieco P, Bonafé M
Center for Applied Biomedical Research (CRBA), St Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
J Pathol. 2008 Jan;214(1):25-37. doi: 10.1002/path.2254.
Basal-like breast carcinoma is an aggressive form of breast cancer, characterized by the absence of oestrogen receptor and HER2 expression, the presence of cytokeratin 5 and epidermal growth factor receptor expression, and by the up-regulation of stem cell regulatory genes. We show here that tumour tissues expressing high levels of SLUG mRNA show a basal-like breast carcinoma phenotype and that such tumours also express high levels of stem cell-regulatory genes, ie CD133, Bmi1. Further, we show that stem/progenitor cells, isolated from ductal breast carcinoma and from normal mammary gland as mammospheres, express SLUG, CD133, and Bmi1 mRNA and show a phenotype similar to that of basal-like breast carcinoma. We also report that SLUG expression in tumour tissues correlates with that of the hypoxia survival gene carbonic anhydrase IX. In this regard, we report that the exposure of SLUG-negative/luminal-like MCF-7 cells to a hypoxic environment promotes the onset of the basal-like breast carcinoma phenotype, together with up-regulation of the SLUG gene, which in turn blunts oestrogen receptor-alpha and boosts carbonic anhydrase IX gene expression. Finally, we show that SLUG expression promotes the invasiveness of MCF-7 cells exposed to hypoxia and sustains the in vivo aggressiveness of hypoxia-selected, MCF-7-derived cells in xenografts. These data indicate that SLUG gene expression is part of a hypoxia-induced genetic programme which sets up a basal/stem cell-like, aggressive phenotype in breast cancer cells.
基底样乳腺癌是一种侵袭性乳腺癌，其特征是缺乏雌激素受体和HER2表达，存在细胞角蛋白5和表皮生长因子受体表达，以及干细胞调节基因上调。我们在此表明，表达高水平SLUG mRNA的肿瘤组织呈现基底样乳腺癌表型，并且此类肿瘤还表达高水平的干细胞调节基因，即CD133、Bmi1。此外，我们表明，从导管乳腺癌和正常乳腺中分离为乳腺球的干/祖细胞表达SLUG、CD133和Bmi1 mRNA，并呈现与基底样乳腺癌相似的表型。我们还报告，肿瘤组织中SLUG的表达与缺氧存活基因碳酸酐酶IX的表达相关。在这方面，我们报告，将SLUG阴性/管腔样MCF-7细胞暴露于缺氧环境会促进基底样乳腺癌表型的出现，同时SLUG基因上调，这反过来会减弱雌激素受体α并增强碳酸酐酶IX基因表达。最后，我们表明，SLUG表达促进暴露于缺氧环境的MCF-7细胞的侵袭性，并维持缺氧选择的、MCF-7衍生细胞在异种移植中的体内侵袭性。这些数据表明，SLUG基因表达是缺氧诱导的遗传程序的一部分，该程序在乳腺癌细胞中建立了一种基底/干细胞样的侵袭性表型。
