RUNX1-dependent mechanisms in biological control and dysregulation in cancer

Abstract

The RUNX1 transcription factor has recently been shown to be obligatory for normal development. RUNX1 controls the expression of genes essential for proper development in many cell lineages and tissues including blood, bone, cartilage, hair follicles, and mammary glands. Compromised RUNX1 regulation is associated with many cancers. In this review, we highlight evidence for RUNX1 control in both invertebrate and mammalian development and recent novel findings of perturbed RUNX1 control in breast cancer that has implications for other solid tumors. As RUNX1 is essential for definitive hematopoiesis, RUNX1 mutations in hematopoietic lineage cells have been implicated in the etiology of several leukemias. Studies of solid tumors have revealed a context-dependent function for RUNX1 either as an oncogene or a tumor suppressor. These RUNX1 functions have been reported for breast, prostate, lung, and skin cancers that are related to cancer subtypes and different stages of tumor development. Growing evidence suggests that RUNX1 suppresses aggressiveness in most breast cancer subtypes particularly in the early stage of tumorigenesis. Several studies have identified RUNX1 suppression of the breast cancer epithelial-to-mesenchymal transition. Most recently, RUNX1 repression of cancer stem cells and tumorsphere formation was reported for breast cancer. It is anticipated that these new discoveries of the context-dependent diversity of RUNX1 functions will lead to innovative therapeutic strategies for the intervention of cancer and other abnormalities of normal tissues.

Keywords: RUNX1; breast cancer; cancer; hematopoiesis; leukemia; mammary gland development.

Figure 1.. Protein domains within RUNX factors.

The protein domains within RUNX1 are diagrammed including the Runt Homology Domain (RHD, DNA and CBF-β binding), Nuclear Localization Signal (NLS), Nuclear Matrix Targeting Signal (NMTS), Activation Domain (AD), Inhibitory Domain (ID), and VWRPY domains. The exons of RUNX1 that correspond to these domains are also shown. Diagrams of the three RUNX factors are displayed. RUNX2 also contains a polyglutamate-alanine rich QA domain.

Figure 2.. Mutations in the Runt Homology Domain of RUNX1 in breast cancer.

Ribbon representation showing CBF-β in purple, DNA binding Runt Homology Domain in green, and DNA in blue. RUNX1 mutations identified in breast cancer patients are shown in red. For clarity, the structure is shown in two different orientations (front and side), rotated 90 degrees relative to one another. The image was rendered from the Public Data Base (PDB) code 1H9D (Bravo, Li, Speck, & Warren, 2001). The locations of the mutations are in the DNA binding domain suggesting RUNX1 loses its putative function in breast tumors.