Department of Breast and Endocrine Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Cancer Sci. 2011 Feb;102(2):439-45. doi: 10.1111/j.1349-7006.2010.01801.x. Epub 2010 Dec 7.
FBXW7 is a cell cycle regulatory gene that ubiquitinates positive cell cycle regulators such as c-Myc and cyclin E, allowing for cell cycle exit. Defects in the FBXW7 gene that lead to cell cycle re-entry and expedite the G1-S transition is thought to be one of the causes of cancer development. However, its clinical importance for breast cancer patients remains undetermined. This prompted us to investigate its expression level in breast cancer patients to establish its clinical significance. The expression level of FBXW7 mRNA was assessed in 186 cases of primary invasive breast cancer. Correlations between FBXW7 mRNA expression and clinicopathological factors, prognoses and immunohistochemical expression levels of Ki-67, FBXW7, c-Myc and cyclin E were analyzed. In vitro investigation of FBXW7 gene silencing in a breast cancer cell line was conducted. FBXW7 mRNA was expressed at significantly lower levels in patients with high histological grade and hormone receptor-negative tumors. Patients with lower FBXW7 mRNA expression had a poorer prognosis for breast cancer-specific survival than those with higher expression. A high Ki-67 labeling index and positive cyclin E protein expression were significantly correlated with lower FBXW7 mRNA expression. In vitro, silencing FBXW7 enhanced expression of c-Myc and cyclin E proteins and upregulated both cell proliferation and G1-S transition. In breast cancer, reduced FBXW7 mRNA expression may have independent prognostic potential through the enhanced function of cell cycle regulatory proteins.
FBXW7 是一个细胞周期调控基因，它使 c-Myc 和细胞周期蛋白 E 等阳性细胞周期调节剂发生泛素化，从而允许细胞周期退出。导致细胞周期重新进入并加速 G1-S 过渡的 FBXW7 基因缺陷被认为是癌症发展的原因之一。然而，其对乳腺癌患者的临床重要性仍未确定。这促使我们研究其在乳腺癌患者中的表达水平，以确定其临床意义。评估了 186 例原发性浸润性乳腺癌患者中 FBXW7 mRNA 的表达水平。分析了 FBXW7 mRNA 表达与临床病理因素、预后以及 Ki-67、FBXW7、c-Myc 和细胞周期蛋白 E 的免疫组化表达水平之间的相关性。在乳腺癌细胞系中进行了 FBXW7 基因沉默的体外研究。高组织学分级和激素受体阴性肿瘤患者的 FBXW7 mRNA 表达水平明显降低。FBXW7 mRNA 表达水平较低的患者乳腺癌特异性生存预后较表达水平较高的患者差。高 Ki-67 标记指数和 cyclin E 蛋白阳性与 FBXW7 mRNA 表达水平降低显著相关。体外，沉默 FBXW7 可增强 c-Myc 和细胞周期蛋白 E 蛋白的表达，并上调细胞增殖和 G1-S 过渡。在乳腺癌中，通过增强细胞周期调控蛋白的功能，降低 FBXW7 mRNA 表达可能具有独立的预后潜力。
