Abstract 451: Clinical potential of the miR-200 - ZEB EMT pathway in cancer
Authors: Linda M. Bojmar, Elin Karlsson, Sander Ellegård, Per A. Sandström, Olle Stål
Journal: Cancer Research (2012)

Abstract The majority of all cancer deaths are caused by metastases rather than the primary tumour. The process by which cells can develop migratory properties is suggested to occur through an epithelial-mesenchymal transition (EMT). The microRNA (miR) 200 family have been associated with EMT and acts negatively on ZEB1 which is a repressor of CDH1 (E-cadherin) thereby supports the epithelial maintenance. Our aim was to investigate the expression of the EMT markers ZEB1, CDH1, miR-200c and miR141 in metastatic colorectal cancer and primary breast tumours and to explore their prognostic significance as well as their correlations to clinicopathological factors. Matched tissue from primary tumour and liver metastasis of 10 colorectal cancer patients and another 15 tissues from CR liver metastasis were used in this study. Moreover, primary tumours from 90 stage II breast tumours from postmenopausal patients, randomized to radiotherapy vs chemotherapy as well as tamoxifen or no endocrine treatment, were included. microRNA and gene expression was studied by quantitative real-time PCR. Correlations between the mir-200 family and CDH1 and inverse correlations to ZEB were found in 15 CR liver metastases as well as in the breast cancer material. In the breast cancer material the gene expression of CDH1 was confirmed by positive correlation to CNV of the CDH1 gene. In the liver metastases low CDH1 was associated with recurrence. A reduction in the mir-200 family was seen in matched normal CR mucosas, primary CRC tumours and liver metastasis and lower expression was found in metastatic CRC primary tumours compared to non-metastatic. In the breast cancer material, wild-type p53 was associated with high expression of the miR cluster which is in agreement with recently presented data of p53 as a suggested regulator of the EMT pathway, via the miR-200 family. In addition, low miR-141/200 expression was associated with activation of the PI3K/AKT pathway, especially in combination with a wild-type p53. miR-141 correlated with positive oestrogen receptor (ER) status, whereas miR200c negatively correlated with HER2 status, suggesting that these miRs may play different roles in different subtypes of breast cancer. A low expression of the miR cluster was associated with a worse outcome in terms of a decreased distant recurrence-free survival. In addition, the levels of miR141/200c were associated with the response to radiation and chemotherapy. Among patients carrying tumours with low miR-141/200c expression, chemotherapy significantly reduced the risk of distant metastases, whereas a high expression of miR141/200c predicted good benefit from radiation, using local or distant recurrence-free survival as an endpoint. These findings support the role of miR141/200c in metastatic progression, and indicate that these markers of EMT could be useful prognostic and treatment predictive factors in cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 451. doi:1538-7445.AM2012-451