Cyclin A1 Modulates the Expression of Vascular Endothelial Growth Factor and Promotes Hormone-Dependent Growth and Angiogenesis of Breast Cancer

Alterations in cellular pathways related to both endocrine and vascular endothelial growth factors (VEGF) may contribute to breast cancer progression. Inhibition of the elevated levels of these pathways is associated with clinical benefits. However, molecular mechanisms by which endocrine-related pathways and VEGF signalling cooperatively promote breast cancer progression remain poorly understood. In the present study, we show that the A-type cyclin, cyclin A1, known for its important role in the initiation of leukemia and prostate cancer metastasis, is highly expressed in primary breast cancer specimens and metastatic lesions, in contrasting to its barely detectable expression in normal human breast tissues. There is a statistically significant correlation between cyclin A1 and VEGF expression in breast cancer specimens from two patient cohorts (p<0.01). Induction of cyclin A1 overexpression in breast cancer cell line MCF-7 results in an enhanced invasiveness and a concomitant increase in VEGF expression. In addition, there is a formation of protein–protein complexes between cyclin A1 and estrogen receptor ER-α cyclin A1 overexpression increases ER-α expression in MCF-7 and T47D cells. In mouse tumor xenograft models in which mice were implanted with MCF-7 cells that overexpressed cyclin A1 or control vector, cyclin A1 overexpression results in an increase in tumor growth and angiogenesis, which is coincident with an enhanced expression of VEGF, VEGFR1 and ER-α Our findings unravel a novel role for cyclin A1 in growth and progression of breast cancer, and suggest that multiple cellular pathways, including cell cycle regulators, angiogenesis and estrogen receptor signalling, may cooperatively contribute to breast cancer progression.

与内分泌通路及血管内皮生长因子（vascular endothelial growth factor, VEGF）相关的细胞通路异常，可能参与乳腺癌的进展过程。靶向抑制此类异常激活的通路，已被证实可带来临床获益。然而，内分泌相关通路与VEGF信号通路协同促进乳腺癌进展的具体分子机制，目前仍未被完全阐明。本研究发现，此前被证实与白血病发生及前列腺癌转移密切相关的A型细胞周期蛋白——细胞周期蛋白A1（cyclin A1），在原发性乳腺癌组织样本及转移灶中呈高表达，而在正常人体乳腺组织中其表达量极低，几乎无法检测到。对两队列乳腺癌患者样本的分析显示，细胞周期蛋白A1的表达与VEGF的表达呈显著统计学正相关（p<0.01）。在乳腺癌细胞系MCF-7中诱导细胞周期蛋白A1过表达，可显著增强细胞侵袭能力，并伴随VEGF表达水平的上调。此外，细胞周期蛋白A1与雌激素受体α（estrogen receptor α, ER-α）可形成蛋白-蛋白复合物；且在MCF-7与T47D细胞中，细胞周期蛋白A1过表达可上调ER-α的表达水平。在构建的小鼠肿瘤异种移植模型中（将过表达细胞周期蛋白A1的MCF-7细胞或空载体对照细胞接种于小鼠体内），细胞周期蛋白A1过表达可促进肿瘤生长与血管生成，同时伴随VEGF、血管内皮生长因子受体1（vascular endothelial growth factor receptor 1, VEGFR1）及ER-α表达水平的上调。本研究结果揭示了细胞周期蛋白A1在乳腺癌生长与进展中的全新作用，并提示包括细胞周期调控因子、血管生成通路及雌激素受体信号通路在内的多条细胞通路，可协同促进乳腺癌的发生发展。