Runx2 in normal tissues and cancer cells: A developing story
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
References (76)
- et al.
Runx2 induces acute myeloid leukemia in cooperation with Cbfbeta-SMMHC in mice
Blood
(2009) - et al.
Loss of Runx1 perturbs adult hematopoiesis and is associated with a myeloproliferative phenotype
Blood
(2005) - et al.
Runx family genes, niche, and stem cell quiescence
Blood Cells Mol. Dis.
(2010) - et al.
Expression of AML/Runx and ETO/MTG family members during hematopoietic differentiation of embryonic stem cells
Exp. Hematol.
(2007) - et al.
Gene-expression profiling and array-based CGH classify CD4+ CD56+ hematodermic neoplasm and cutaneous myelomonocytic leukemia as distinct disease entities
Blood
(2007) - et al.
Spatial and temporal expression pattern of Runx3 (Aml2) and Runx1 (Aml1) indicates non-redundant functions during mouse embryogenesis
Mech. Dev.
(2001) - et al.
Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development
Cell
(1997) - et al.
The osteoblast transcription factor Runx2 is expressed in mammary epithelial cells and mediates osteopontin expression
J. Biol. Chem.
(2003) - et al.
Positive association between nuclear Runx2 and oestrogen–progesterone receptor gene expression characterises a biological subtype of breast cancer
Eur. J. Cancer
(2009) - et al.
Runx2 regulates survivin expression in prostate cancer cells
Lab. Invest.
(2010)
RNAi-mediated silencing of TEL/AML1 reveals a heat-shock protein- and survivin-dependent mechanism for survival
Blood
Parathyroid hormone regulates the rat collagenase-3 promoter in osteoblastic cells through the cooperative interaction of the activator protein-1 site and the runt domain binding sequence
J. Biol. Chem.
The vitamin D receptor, Runx2, and the Notch signaling pathway cooperate in the transcriptional regulation of osteopontin
J. Biol. Chem.
Tumor–stroma co-evolution in prostate cancer progression and metastasis
Semin. Cell Dev. Biol.
Regulation of human osteocalcin promoter in hormone-independent human prostate cancer cells
J. Biol. Chem.
The RUNX genes: gain or loss of function in cancer
Nat. Rev. Cancer
til-1: a novel proviral insertion locus for Moloney murine leukaemia virus in lymphomas of CD2-myc transgenic mice
J. Gen. Virol.
Proviral insertions induce the expression of bone-specific isoforms of PEBP2alphaA (CBFA1): evidence for a new myc collaborating oncogene
Proc. Nat. Acad. Sci. U.S.A.
A full-length Cbfa1 gene product perturbs T-cell development and promotes lymphomagenesis in synergy with myc
Oncogene
Runx2: a novel oncogenic effector revealed by in vivo complementation and retroviral tagging
Oncogene
Runx2 and MYC collaborate in lymphoma development by suppressing apoptotic and growth arrest pathways in vivo
Cancer Res.
Identification of genes that synergize with Cbfb–MYH11 in the pathogenesis of acute myeloid leukemia
Proc. Nat. Acad. Sci. U.S.A.
The leukemic protein core binding factor beta (CBFbeta)-smooth-muscle myosin heavy chain sequesters CBFalpha2 into cytoskeletal filaments and aggregates
Mol. Cell Biol.
The inv(16) encodes an acute myeloid leukemia 1 transcriptional corepressor
Proc. Nat. Acad. Sci. U.S.A.
The inv(16) fusion protein associates with corepressors via a smooth muscle myosin heavy-chain domain
Mol. Cell Biol.
Enforced expression of Runx2 perturbs T cell development at a stage coincident with beta-selection
J. Immunol.
AML-1 is required for megakaryocytic maturation and lymphocytic differentiation, but not for maintenance of hematopoietic stem cells in adult hematopoiesis
Nat. Med.
TEL–AML1 preleukemic activity requires the DNA binding domain of AML1 and the dimerization and corepressor binding domains of TEL
Oncogene
Discriminating gene expression profiles of memory B cell subpopulations
J. Exp. Med.
Human myeloma cells express the bone regulating gene Runx2/Cbfa1 and produce osteopontin that is involved in angiogenesis in multiple myeloma patients
Leukemia
Pathogenesis of myeloma bone disease
J. Cell Biochem.
Loss of Runx3 affects ovulation and estrogen-induced endometrial cell proliferation in female mice
Mol. Reprod. Dev.
A differential gene expression profile reveals overexpression of RUNX1/AML1 in invasive endometrioid carcinoma
Cancer Res.
An orthotopic endometrial cancer mouse model demonstrates a role for RUNX1 in distant metastasis
Int. J. Cancer
Gene expression profiling of the rat endometriosis model
Am. J. Reprod. Immunol.
Gene expression profiling of leiomyoma and myometrial smooth muscle cells in response to transforming growth factor-beta
Endocrinology
Changes in mouse granulosa cell gene expression during early luteinization
Endocrinology
Development and application of a rat ovarian gene expression database
Endocrinology
Cited by (83)
Dendritic cell vaccines in breast cancer: Immune modulation and immunotherapy
2023, Biomedicine and PharmacotherapyRunx transcription factors in the development and function of the definitive hematopoietic system
2017, BloodCitation Excerpt :In mammals, Runx1 was first identified as a critical regulator of hematopoiesis,7,8 Runx2 for its role in bone development,9,10 and Runx3 for its requirement in neurogenesis.11 However, all 3 factors were later shown to play critical roles also in other organ systems,12-14 and it is now clear that not only Runx1 but also Runx2 and Runx3 play a part in hematopoiesis. Cbfβ, the heterodimeric non–DNA-binding partner protein of the Runx factors, is also critical for hematopoiesis; without it, the Runx factors cannot bind DNA efficiently to regulate expression of their target genes.15
RUNX regulated immune-associated genes predicts prognosis in breast cancer
2022, Frontiers in Genetics
- 1
Current address: Victorian Breast Cancer Research Consortium, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Melbourne, VIC 3050, Australia.