Cancers associated with alterations to CBF

Alterations to CBF activity result in human disease. For example, human RUNX1 was first identified as the target of the t(8;21) chromosomal translocation associated with acute myelogenous leukemia (AML) [20, 47]. The t(8;21) is associated with approximately 12% of AML cases [48]. The t(8;21) results in the production of a chimeric transcription factor that retains the RUNX1 (chromosome 21) DNA binding domain but replaces the entire C-terminus with MTG8 (also called ETO), a transcriptional co-repressor [24, 49, 50]. RUNX1 is also the target of the rarer t(16;21) found in both de novo and therapy-related AML [51] and the t(12;21) identified in pre-B-cell acute lymphoblastic leukemia (ALL) [52]. These translocations fuse the RUNX1 DNA binding domain to an ETO-related protein termed MTG16 (CBFA2T3) and to an ETS-related transcription factor, respectively, to create chimeric gene regulatory factors [51, 52]. CBFp is also targeted by genomic abnormalities that lead to AML. For example, the pericentric inversion of chromosome 16 produces a chimeric CBFp/smooth muscle myosin heavy chain (SMMHC) protein termed CBFp-SMMHC [53]. These chimeric transcription factors are thought to contribute to leukemogenesis by interfering with CBF-regulated transcription [54]. Moreover, these chromosomal abnormalities demonstrate that CBF alterations can result in both lymphoid and myeloid leukemias.

CBF's role in blood development and in leukemia was brought into sharp focus by animal studies and by the identification of the molecular defects associated with AML. For many years, RUNX1 was considered blood specific, in part because of the strong phenotype obtained in Runxl-null mice. More recently, the expression, composition and function of CBF was studied in a wide variety of normal and cancerous cell lines and tissues. For example, RUNX protein expression was identified in the hair follicle stem cells (HFSCs) of the skin, and CBF is required to regulate HFSC proliferation [55]. Moreover, RUNX1 expression is activated in a chemical-induced model of rodent skin squamous cell carcinoma [55].

The expression of RUNX factors in prostate epithelial cell lines and normal prostate tissue was identified by real-time RT-PCR [56]. RUNX1, RUNX2, and RUNX3 were variously expressed in normal prostate tissue, an immortalized, non-transformed cell line, prostate cancer cell lines and primary prostate cancers [56]. To confirm that mRNA expression led to active DNA binding activity, CBF presence was confirmed using electrophoretic mobility shift assay (EMSA) [56]. While RUNX1 and RUNX2 were always expressed in prostate cancer cell lines, RUNX3 expression was not observed in most prostate cancer cell lines [56]. This correlates well with other studies that have identified RUNX2 expression in prostate cancer cell lines and showed that decreasing RUNX2 expression inhibits cell growth [57]. RUNX2 may play a role in tumor spread since RUNX2 triggers expression of bone-specific genes in prostate cancers, which may be involved in bone metastasis [58, 59]. Moreover, in a PTEN-deleted mouse model of prostate cancer, developing tumors increased Runx2 expression [60]. Thus, there is evidence that Runx2 expression is increased in malignant versus benign prostate tissue and is associated with tumor metastasis [61]. Interestingly, in a study of 314 patients with clinically localized prostate cancer that were treated with radical prostatectomy, the allelic variant RUNX1 rs2253319 was associated with metastasis to lymph nodes [62]. These data illustrate both the complexity of CBF expression in prostate and the involvement of CBF in cancer growth and metastasis. CBF is also highly expressed or altered in lung, endometrioid, and breast cancers [63-65].

CBF interacts with steroid hormones in various tissues. For example, the vitamin D receptor (VDR) associates with RUNX2 to regulate osteocalcin gene expression [66] and inappropriate expression of osteocalcin in prostate cancer cells depends upon RUNX2 [38]. CBF also interacts with the androgen receptor. RUNX1 and RUNX2 have both been shown to activate transcription from the prostate specific antigen (PSA) promoter and RUNX1 and RUNX2 physically associate with the AR [56] [57]. In prostate cancer cell lines, RUNX2 enhances TGF-p and androgen response [57]. Thus, the CBF and AR transcriptional pathways intersect in a way that enhances AR signaling. These data suggest that targeting CBF in prostate tumors should negatively impact AR signaling as well.

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