KAI1, a metastasis suppressor gene for human breast cancer.

摘要

The KAI1 gene maps to chromosome 11p11.2. KAI1 is a metastasis suppressor gene for human prostate cancer and is also involved in the progression of a variety of other human cancers such as pancreatic cancer, bladder cancer, non-small cell lung cancer, melanoma, colon cancer, breast cancer, gastric cancer, hepatocellular carcinoma, and oesophageal squamous cell carcinoma. The aim of our study is to determine whether KAI1 expression is related to breast cancer metastasis. By Northern blot, Western blot and immunostaining analyses, we compared the metastatic propensity and invasive ability of a continuum of breast cancer cells with varying degrees of progression toward malignancy and found that these parameters tended to correlate inversely with KAI1 mRNA and protein expression. Furthermore, we examined KAI1 protein expression immunohistochemically in 81 specimens from patients with breast cancer and correlated the findings with clinical and histopathological parameters. The results showed that more malignant tumors demonstrated a significantly lower expression of KAI1 (P 0.004). Of the 29 specimens that contain multiple types of tumor grade, 23 demonstrated differences in KAI1 expression. That is, the more malignant cells within an individual specimen, the lower the KAI1 expression as compared to less or non-malignant cells in the same specimen (P 0.001). Transfection of full length KAI1 cDNA into LCC6, a highly metastatic breast cancer cell line, resulted in a significant suppression of both spontaneous and experimental metastasis in vivo. Metastasis suppression correlated with a reduced rate of tumor growth, tumorigenicity and a decreased clonogenicity in soft agar. Moreover, overexpression of KAI1 into a highly invasive breast cancer cell line, MDA-MB-231, resulted in a significant reduction of cells invading through the reconstituted basement membrane. These data suggest that, in addition to its role in human prostate cancer, KAI1 may also function as a metastasis suppressor gene for human breast cancer. The precise molecular mechanism of how KAI1 exerts its effect on breast cancer metastasis is not yet clear. The suppressive effect of KAI1 on breast cancer invasion and metastasis appears not to be mediated through its interference with cell cycle, apoptosis, motility, adhesion to ECM components, phagocytosis and degradative enzymes. By cDNA array assay, we found that expression levels of some genes were changed by overexpression of KAI1. Among them, the expression of oncogenes c-myc, cyclin G1 was reduced 4 fold, the expression of CD44, an adhesion and metastasis related molecule, was reduced 3 fold. In addition, the expression of some transcription factors was also reduced about 2–3 fold. Further studies are necessary to elucidate the molecular pathways which may be regulated by KAI1.