Lee Connie W, Simin Karl, Liu Qin, Plescia Janet, Guha Minakshi, Khan Ashraf, Hsieh Chung-Cheng, Altieri Dario C
Department of Cancer Biology, Cancer Center, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA.
Breast Cancer Res. 2008;10(6):R97. doi: 10.1186/bcr2200. Epub 2008 Nov 24.
Basal-type, or triple-negative, breast cancer (lacking estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 expression) is a high-risk disease for which no molecular therapies are currently available. We studied genetic signatures of basal breast cancer potentially suitable for therapeutic intervention.
We analyzed protein expression of the Notch-1 intracellular domain and survivin by immunohistochemistry in a series of basal breast cancer patients. A hierarchical clustering and overall survival analysis was carried out on a microarray mRNA database of 232 breast cancer patients. Fifteen published mRNA datasets containing estrogen receptor-negative or estrogen receptor-positive samples were subjected to meta-analysis for co-segregated gene expression. Experiments of plasmid transfection and gene silencing were carried out in estrogen receptor-negative MDA-MB-231 breast cancer cells.
The developmental signaling regulator Notch-1 was highly expressed in breast cancer, compared with normal tissue, and was segregated with basal disease. Higher Notch-1 levels correlated with progressively abbreviated overall survival, and with increased expression of survivin, a tumor-associated cell death and mitotic regulator implicated in stem cell viability. Analysis of Pearson's correlation coefficient indicated that Notch-1 and survivin co-segregated in basal breast cancer. Notch-1 stimulation in MDA-MB-231 cells increased survivin expression, whereas silencing Notch reduced survivin levels.
A Notch-1-survivin functional gene signature is a hallmark of basal breast cancer, and may contribute to disease pathogenesis. Antagonists of Notch and survivin currently in the clinic may be tested as novel molecular therapy for these recurrence-prone patients.
基底样或三阴性乳腺癌（缺乏雌激素受体、孕激素受体和人表皮生长因子受体2表达）是一种高风险疾病，目前尚无分子疗法。我们研究了可能适用于治疗干预的基底样乳腺癌的基因特征。
我们通过免疫组织化学分析了一系列基底样乳腺癌患者中Notch-1细胞内结构域和生存素的蛋白表达。对232例乳腺癌患者的微阵列mRNA数据库进行了层次聚类和总生存分析。对15个已发表的包含雌激素受体阴性或雌激素受体阳性样本的mRNA数据集进行了共分离基因表达的荟萃分析。在雌激素受体阴性的MDA-MB-231乳腺癌细胞中进行了质粒转染和基因沉默实验。
与正常组织相比，发育信号调节因子Notch-1在乳腺癌中高表达，并与基底样疾病相关。Notch-1水平越高，总生存期越短，且与生存素表达增加相关，生存素是一种与肿瘤相关的细胞死亡和有丝分裂调节因子，与干细胞活力有关。Pearson相关系数分析表明，Notch-1和生存素在基底样乳腺癌中共分离。在MDA-MB-231细胞中刺激Notch-1可增加生存素表达，而沉默Notch则降低生存素水平。
Notch-1-生存素功能基因特征是基底样乳腺癌的标志，可能与疾病发病机制有关。目前临床上的Notch和生存素拮抗剂可作为这些易复发患者的新型分子疗法进行测试。
