Zhuang Zhi-Gang, Di Gen-Hong, Shen Zhen-Zhou, Ding Jian, Shao Zhi-Ming
Breast Cancer Institute, Cancer Hospital, Department of Oncology, Shanghai Medical College, Institutes of Biomedical Science, Fudan University, Shanghai, People's Republic of China.
Mol Cancer Res. 2006 Nov;4(11):843-9. doi: 10.1158/1541-7786.MCR-06-0118.
LKB1 (also known as STK11) is a recently identified tumor suppressor gene whose mutation can lead to Peutz-Jeghers syndrome, which is characterized by gastrointestinal polyps and cancers of different organ systems. Approximately 30% of sporadic breast cancer samples express low levels of LKB1. This suggests that the LKB1 gene may be related to the tumorigenesis of breast cancer. We reintroduced LKB1 into MDA-MB-435 breast cancer cells that lack the LKB1 gene to investigate how overexpression of LKB1 affects tumor invasiveness and metastasis. Overexpression of the LKB1 protein in breast cancer cells resulted in significant inhibition of in vitro invasion. In vivo, LKB1 expression reduced tumor growth in the mammary fat pad, microvessel density, and lung metastasis. LKB1 overexpression was associated with down-regulation of matrix metalloproteinase-2, matrix metalloproteinase-9, vascular endothelial growth factor, and basic fibroblast growth factor mRNA and protein levels. Overexpression of the LKB1 protein in human breast cancer is significantly associated with a decrease in microvessel density. Our results indicate that LKB1 plays a negative regulatory role in human breast cancer, a finding that may lead to a new therapeutic strategy.
LKB1（也称为STK11）是最近发现的一种肿瘤抑制基因，其突变可导致黑斑息肉综合征，其特征为胃肠道息肉和不同器官系统的癌症。大约30%的散发性乳腺癌样本中LKB1表达水平较低。这表明LKB1基因可能与乳腺癌的肿瘤发生有关。我们将LKB1重新导入缺乏LKB1基因的MDA-MB-435乳腺癌细胞中，以研究LKB1的过表达如何影响肿瘤的侵袭性和转移。乳腺癌细胞中LKB1蛋白的过表达导致体外侵袭受到显著抑制。在体内，LKB1表达降低了乳腺脂肪垫中的肿瘤生长、微血管密度和肺转移。LKB1过表达与基质金属蛋白酶-2、基质金属蛋白酶-9、血管内皮生长因子和碱性成纤维细胞生长因子的mRNA及蛋白水平下调相关。人乳腺癌中LKB1蛋白的过表达与微血管密度降低显著相关。我们的结果表明，LKB1在人乳腺癌中起负调控作用，这一发现可能会带来新的治疗策略。
