Oncogenic mutation in RAS-RAF axis leads to increased expression of GREB1, resulting in tumor proliferation in colorectal cancer.

BRAF^V600E mutation accounts for up to 90% of all BRAF mutations in human colorectal cancer (CRC), and constitutively activates the MEK-MAPK pathway. It is recognized that neutralizing mAbs for epidermal growth factor receptor alone are not effective for CRC with BRAF^V600E mutation. Therefore, there is increasing interest in identification of the possible therapeutic targets in downstream of BRAF mutation in CRCs. To address this, we studied genome engineered mouse models for colonic neoplasia that has Braf^V600E mutation on the basis of Apc inactivation, induced in 2 distinct Cre mouse models, CDX2P-G22Cre and CDX2P-CreER^T2 mice. We carried out oligonucleotide microarray analysis for colonic neoplasia generated in these mouse models, and compared gene expression profiles among Kras/Braf WT, Kras-mutated, and Braf-mutated mouse colon tumors to seek new molecular targets corresponding to the KRAS-BRAF-MAPK axis. We found that the expression of the growth regulation by estrogen in breast cancer protein 1 (Greb1) was the most upregulated gene in Braf-mutated mouse tumors compared to Kras/Braf WT counterparts. The silencing of GREB1 significantly reduced the proliferation and tumorigenesis of CRC cell lines, whereas the overexpression of GREB1 promoted cell proliferation. Although GREB1 was first identified as a hormone-responsive gene mediating estrogen-stimulated cell proliferation in endometriosis, breast, and ovarian cancers, these results suggest that RAS-RAF-MAPK signaling upregulates GREB1 expression in CRC, resulting in cellular proliferation. Thus, GREB1 is a possible therapeutic target for CRCs with Braf^V600E mutation.

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