Bièche I, Olivi M, Noguès C, Vidaud M, Lidereau R
Laboratoire de Génétique Moléculaire-UPRES JE 2195, Faculté des Sciences Pharmaceutiques et Biologiques, Université René Descartes-Paris V, 4 Avenue de l'Observatoire, F-75006 Paris, France.
Br J Cancer. 2002 Feb 12;86(4):580-6. doi: 10.1038/sj.bjc.6600109.
The CCND1 gene, a key cell-cycle regulator, is often altered in breast cancer, but the mechanisms underlying CCND1 dysregulation and the clinical significance of CCND1 status are unclear. We used real-time quantitative PCR and RT-PCR assays based on fluorescent TaqMan methodology to quantify CCND1 gene amplification and expression in a large series of breast tumours. CCND1 overexpression was observed in 44 (32.8%) of 134 breast tumour RNAs, ranging from 3.3 to 43.7 times the level in normal breast tissues, and correlated significantly with positive oestrogen receptor status (P=0.0003). CCND1 overexpression requires oestrogen receptor integrity and is exacerbated by amplification at 11q13 (the site of the CCND1 gene), owing to an additional gene dosage effect. Our results challenge CCND1 gene as the main 11q13 amplicon selector. The relapse-free survival time of patients with CCND1-amplified tumours was shorter than that of patients without CCND1 alterations, while that of patients with CCND1-unamplified-overexpressed tumours was longer (P=0.011). Only the good prognostic significance of CCND1-unamplified-overexpression status persisted in Cox multivariate regression analysis. This study confirms that CCND1 is an ER-responsive or ER-coactivator gene in breast cancer, and points to the CCND1 gene as a putative molecular marker predictive of hormone responsiveness in breast cancer. Moreover, CCND1 amplification status dichotomizes the CCND1-overexpressing tumors into two groups with opposite outcomes.
CCND1基因是一种关键的细胞周期调节因子，在乳腺癌中常发生改变，但CCND1失调的潜在机制以及CCND1状态的临床意义尚不清楚。我们使用基于荧光TaqMan方法的实时定量PCR和RT-PCR检测，对大量乳腺肿瘤中的CCND1基因扩增和表达进行定量。在134个乳腺肿瘤RNA中，有44个（32.8%）观察到CCND1过表达，其水平为正常乳腺组织的3.3至43.7倍，且与雌激素受体阳性状态显著相关（P = 0.0003）。CCND1过表达需要雌激素受体的完整性，并且由于11q13（CCND1基因所在位点）的扩增导致额外的基因剂量效应而加剧。我们的结果对CCND1基因作为主要的11q13扩增子选择因子提出了挑战。CCND1扩增肿瘤患者的无复发生存时间短于无CCND1改变的患者，而CCND1未扩增但过表达肿瘤患者的无复发生存时间更长（P = 0.011）。在Cox多变量回归分析中，只有CCND1未扩增但过表达状态具有良好的预后意义。这项研究证实CCND1是乳腺癌中的一种雌激素受体反应性或雌激素受体共激活基因，并指出CCND1基因是预测乳腺癌激素反应性的一种推定分子标志物。此外，CCND1扩增状态将CCND1过表达肿瘤分为两组，其结果相反。
