Runx2 in normal tissues and cancer cells: A developing story

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Abstract

The Runx transcription factors are essential for mammalian development, most notably in the haematopoietic and osteogenic lineages. Runx1 and its binding partner, CBFβ, are frequently targeted in acute leukaemia but evidence is accumulating that all three Runx genes may have a role to play in a wider range of cancers, either as tumour promoters or tumour suppressors. Whilst Runx2 is renowned for its role as a master regulator of bone development we discuss here its expression pattern and putative functions beyond this lineage. Furthermore, we review the evidence that RUNX2 promotes neoplastic development in haematopoietic lineages and in advanced mammary and prostate cancer.

Introduction

The Runx genes comprise a family of three closely related transcription factors; Runx1, Runx2 and Runx3, which together with a common partner (CBFβ) form the Core Binding Factor (CBF) complex and bind DNA to either activate or repress gene transcription. These genes have been implicated in specific cancers [1] and various knockout models have demonstrated essential roles in various developmental processes. Such models have emphasised headline functions including the importance of Runx1 in multiple haematopoietic lineages, the role of Runx2 in cartilage and bone development and Runx3 function in diverse tissues. In addition to these essential roles in major lineages their widespread spatial and temporal expression indicates that many other crucial functions remain to be established. There is a growing literature on both the oncogenic and tumour suppressive functions of the Runx genes but with the exception of Runx1 in the haematopoietic system an understanding of their relative importance amongst a myriad of oncogenic signalling pathways remains tantalisingly out of reach. Given the breadth of published work and the existence of a number of reviews on different facets of Runx function we have chosen to focus on the role of Runx2 in neoplastic disease in the haematopoietic system and in specific epithelial tissues.

Section snippets

Runx2 and haematopoietic tissues

The strongest evidence for a pro-oncogenic function for Runx2 comes from studies in lymphoma/leukaemia models. The first indication arose from Murine Leukaemia Virus (MLV) acceleration of mice predisposed to T cell lymphoma, as a result of transgenic mediated deregulation of the c-Myc oncogene [2], [3]. In this study a remarkably high incidence of tumours harboured activating viral insertions upstream of the distal promoter of Runx2 resulting in over-expression of the full length wild type

Runx2 and reproductive tissues

Although no crucial Runx-dependent function has yet been established in reproduction, Runx expression marks an intriguing range of relevant tissues. During development both Runx1 [22] and Runx2 are expressed in the Mullerian (paramesonephric) ducts, the rudimentary structure that ultimately forms the uterine tubes, uterus, cervix and upper part of the vagina (Fig. 2b). By contrast expression was absent from the Wolffian (mesonephric) ducts, which form the anlage for certain male reproductive

Runx2 and breast cancer

Runx2 has been found to be expressed in the rudimentary foetal mammary gland [35] and in the developing mammary gland of the pubertal mouse where expression is highest in association with the terminal end buds, the structures from which the mammary epithelial cells derive [36]. Furthermore Runx2 expression regulates genes important for normal mammary function in primary epithelial cells, namely osteopontin and β-casein [37], [38]. We have found that all three Runx genes are expressed at low

Runx2 and prostate cancer

Runx2 is expressed in normal prostate tissues (Fig. 2e) and while its physiological role is unknown, both Runx1 and Runx2 have been shown to regulate prostate specific antigen (PSA) through the presence of Runx binding sites in the regulatory region of the gene [51]. In an intriguing circulatory, PSA expression in osteosarcoma cells can drive a more differentiated phenotype upregulating a number of genes associated with osteoblast differentiation including Runx2 and osteocalcin [52]. A number

Does Runx2 cause preferential metastasis to bone?

A key argument for a role for Runx2 in advanced mammary and prostate cancer arises from the high incidence of spread to skeletal bone. There is good evidence that cancer cells with the capacity to adopt the characteristics of bone cells, known as osteomimicry [69], [70], [71], and stimulate bone remodelling are more likely to successfully colonise this environment and change it in a way that supports further growth. Given that Runx2 is a master regulator of osteoblast differentiation, and can

Prospects

Our understanding of Runx gene action in various lineages and developmental processes and its role in integrating cell fate decisions has made significant progress in the last 15 years. Although a developing story, the importance of Runx1 in the homeostatic regulation of haematopoiesis and the implications for leukaemia are well recognised. Numerous reports on loss of expression or dysregulation of RUNX3 in epithelial cancers have been published in recent years and emphasise the importance of

Acknowledgments

This paper is based on a presentation at the EMBO Workshop on RUNX transcription factors in development and disease, held in Oxford, August 16–19, 2009. This EMBO Workshop was co-sponsored by the NIH Office of Rare Diseases, Company of Biologists, MRC Molecular Haematology Unit, Leukaemia Research Fund, Heinrich Pette Institut, and the Association for International Cancer Research. Work carried out is supported by the Association for International Cancer Research, Cancer Research UK and

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    Current address: Victorian Breast Cancer Research Consortium, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Melbourne, VIC 3050, Australia.

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