The Diverse Role of the ETS Family of Transcription Factors in Cancer Commentary Re: B
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Vol. 7, 451–453, March 2001 Clinical Cancer Research 451 The Biology Behind The Diverse Role of the ETS Family of Transcription Factors in Cancer Commentary re: B. Davidson, Ets-1 Messenger RNA Expression Is a Novel Marker of Poor Survival in Ovarian Carcinoma. Clin. Cancer Res., 7: 551–557, 2001. D. Gary Gilliland1 with Ewing’s sarcoma and the TLS/ERG (12) and ETV6/MN1 Howard Hughes Medical Institute, Brigham and Women’s Hospital, (13) fusion associated with human leukemia. In addition, there Harvard Institutes of Medicine, Harvard Medical School, Boston, is a broad spectrum of hematological malignancies in which the Massachusetts 02115 PNT oligomerization motif is involved in chromosomal trans- locations with a diverse group of partners that include transcrip- Oncogenicity potential was a defining characteristic of tion factors, tyrosine kinases, and genes of unknown function. v-ets, the first of the large family of ETS transcription factors to For example, the ETS translocation variant 6 (also known as Ͼ be cloned. v-ets was discovered as an oncoprotein fusion with TEL) gene is known to be involved in 40 different transloca- gag and myb in the E26 avian erythroblastosis virus (1). There tions in human hematological malignancies. In most of these are now more than 25 ETS family members defined by a DNA cases, balanced reciprocal chromosomal translocations result in binding or ETS domain, which is highly conserved among expression of a fusion protein in which the PNT domain is fused family members, and binds to the core DNA binding motif C/A in-frame to the respective partners. Examples of TEL fusions to GCA A/T. In addition, a subset of ETS family members have a tyrosine kinases include TEL/PDGFR (14, 15), TEL/TRKc highly conserved PNT domain that, at least in some contexts, (16–19), TEL/ABL (20–22), and TEL/JAK2 (23–26), among acts an as oligomerization motif (2). others. TEL may also be fused to transcription factor partners ETS family members play an important role in mammalian such as AML1 (27–31), EVI1 (32), and others. In these exam- development. For example, targeted disruption of the Fli-1 gene ples, there is strong epidemiological support for a direct role in results in hemorrhage from the dorsal aorta to the lumen of the transformation of cells. Although these diseases are rare, with an neural tube and brain ventricles on embryonic day 11.0 (E11.0; incidence of approximately 1 per 100,000 individuals/year, the Ref. 3). Deficiency of Ets2 causes day E8.5 embryonic lethality, chromosomal translocations are highly conserved and in most with defects in extraembryonic tissue gene expression and func- cases result in expression of identical in-frame fusions. In ad- tion and failure of ectoplacental cone proliferation (4). Loss of dition, in some cases it has been possible to demonstrate that the function of ETV6/TEL2 causes E9.5 embryonic lethality with ETS fusion protein is both necessary and sufficient for disease severe defects in yolk sac angiogenesis and apoptosis of neural pathogenesis. For example, the TEL/PDGFR, TEL/TRKc, crest-derived ganglia (5). In addition, ETS family members play TEL/ABL, and TEL/JAK2 fusion proteins are each capable of important roles in hematopoietic development. Disruption of causing myeloproliferative disease in murine bone marrow Ets-1 causes defects in natural killer cell development (6), loss transplant models of leukemia. These observations have of function of PU.1 causes defects in myelopoiesis as well as prompted further analysis of downstream targets that may con- B-lymphopoiesis (7–9), and loss of ETV6/TEL causes inability tribute to malignant transformation of cells. For example, TEL/ for the transition of definitive hematopoietic cells from the liver JAK2 and other TEL tyrosine kinase fusion molecules activated to the bone marrow (10). STAT5, a member of the STAT family of latent cytoplasmic In addition to playing an important role in mammalian transcription factors. In the case of TEL/JAK2, activation of development, ETS family members have been directly impli- STAT5 is both necessary and sufficient to transform hemato- cated in the pathogenesis of a spectrum of human cancers; ETS poietic cells. STAT5, in turn, is known to transactivate a number involvement in human malignancy is notable for pleiotropic of genes that regulate cellular proliferation and survival, such as structural and functional contributions to the contributions to the oncostatin M, Bcl-Xl, cyclin D1, and Pim1 (26). Thus, direct or malignant phenotype (Fig. 1). For example, there is a spectrum indirect transcriptional targets of the ETS fusion proteins con- of cancers that include soft tissue sarcomas and leukemias in tributes directly to the transformed phenotype of the cells. which balanced reciprocal translocations result in fusion pro- Loss of function of ETS family members may also con- teins that contain the ETS DNA binding domain. Examples tribute to the pathogenesis of human cancers. For example, in include the EWS-FLI1 and EWS-ERG (11) fusion associated TEL/AML1 leukemias, there is nearly invariable deletion of the residual TEL allele (27–31, 33, 34). Thus, as a consequence of translocation and deletion, there is no functional TEL present in leukemic cells, suggesting that TEL may have tumor suppressor function. Recently, Mueller et al. (35) have reported the pres- 1 To whom requests for reprints should be addressed, at Howard Hughes ence of mutations in PU.1 associated with human leukemias, Medical Institute, Brigham and Women’s Hospital, Harvard Institute of indicating that the loss of function of PU.1 may also contribute Medicine, Harvard Medical School, 4 Blackfan Circle, Room 418, Boston, MA 02115. to the pathogenesis of disease. 2 The abbreviations used are: TEL, translocation ETS leukemia; In the current report, Davidson et al. (see this issue, pp. PDGFR, platelet-derived growth factor  receptor. 551–557) have provided new and important clinical therapeutic Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2001 American Association for Cancer Research. 452 ETS Family Members and Cancer that the overexpression of ETS-1 in ovarian cancer not only activates transcription of genes required for potentiation of metastasis but contributes directly to the transformation of cells. This study also suggests that it may be of value to analyze the expression of other ETS family members in solid tumors. In addition, it will be important to determine the molecular mech- anisms whereby ETS-1 or other family members are overex- pressed. Are these downstream effectors of transformation me- diated by aberrant trans-acting elements, or are their cis-acting mutations that confer are responsible for the overexpression of ETS-1. Finally, these data, with the limited spectrum of target genes analyzed, suggest that efforts to identify global gene expression signatures for epithelial tumors characterized by ETS-1 overexpression may identify additional target genes that Fig. 1 Diverse mechanisms for contributing to the cancer phenotype are potential prognostic factors or targets for therapy. by ETS family members. These include fusion of the PNT oligomer- Taken together, this analysis has identified a new potential ization motif to a spectrum of partners, including tyrosine kinases such marker for prognosis in ovarian carcinomas and provides indi- as PDGFR, ABL, JAK2, and TRKC, as well as transcription factors rect support for the hypothesis that ETS-1 expression regulates such as AML1. In addition, the ETS, or DNA binding domain, is fused to partners that are thought to confer transactivating function, such as expression of proteinases and angiogenic factors that impact EWS, in soft tissue sarcomas and in some leukemias. There is evidence clinical behavior and response to therapy. The study provides that loss of function of ETS family members may contribute to trans- fertile new ground for investigation of the molecular basis of the formation, including the loss of function of both TEL (ETV6) alleles in correlation between ETS-1 expression and genes that may po- TEL/AML1 pediatric acute lymphoblastic leukemias and loss of func- tion mutations of PU.1 in acute myeloid leukemia. Finally, there is tentiate the malignant phenotype, as well as testing these obser- evidence, as described by Davidson et al. in this report, that overex- vations in cell culture and vertebrate models of disease patho- pression of ETS family members and transactivation of their down- genesis. stream target genes contribute to the malignant phenotype. These studies also provide a cogent reminder that the ability to transform an epithelial cell is only a part of the spectrum of biological activities that a transforming oncoprotein insights into another role of ETS family members in human confers on the malignant phenotype. Further investigations of cancer. In addition to direct contributions to the transformed the spectrum of genes that are expressed in tumor cells using phenotype, aberrant overexpression of ETS family members sophisticated global expression analysis may shed additional may influence metastatic potential and response to therapy of insights on transcriptional regulatory networks that contribute to certain human epithelial tumors. Davidson et al. assayed ETS-1 disease pathogenesis. expression using mRNA in situ hybridization from 66 primary ovarian carcinomas and metastatic lesions obtained from 41 References patients diagnosed with advanced stage ovarian carcinoma. 1. Nunn, M., Seeburg, P. H., Moscovici, C., and Duesberg, P. H. ETS-1 expression was detected in 42 and 33%, respectively, of Tripartite structure of the avian erythroblastosis virus E26 transforming carcinoma and stromal cells, respectively. There was a statisti- gene. Nature (Lond.), 306: 391–395, 1983. cally significant correlation between ETS-1 and VEGF expres- 2. Wasylyk, B., Hahn, S. L., and Giovane, A. The Ets family of sion in carcinoma and stromal cells, basic fibroblast growth transcription factors. Eur. J. Biochem., 211: 7–18, 1993.