ReviewThe role of the transcription factor Ets1 in carcinoma
Introduction
Cancer is a leading cause of death worldwide, having killed 8.2 million people in 2012 [1]. Most cancers originate from epithelial cells. The incidence of these carcinomas is different in women and men. In women, breast carcinoma is the most commonly diagnosed cancer and leading cause of the cancer deaths around the world, whereas, in men, it is lung cancer. Each cancer type has its specific biology and even within a cancer type several subtypes may exist that show different addictions to signaling pathways and proteins and are associated with different outcomes for the patients. In breast cancer, the ERα (estrogen receptor α)-positive subtype is linked to a more favorable survival than the Her2 (human epidermal receptor 2)-positive subtype or the triple-negative (no ERα, no progesterone receptor, no Her2) subtype or, based on gene expression profiling (molecular taxonomy), luminal-A-like cancers (mostly ERα-positive) predict a better survival than luminal B-like (mostly ERα-positive), Her2-enriched (mostly Her2-positive) or basal-like (mostly triple-negative) cancers [2]. Besides the specific biology of a cancer type or a subtype, the availability of effective treatments against the type/subtype and the tendency of a type/subtype to develop drug resistance determine the survival probability of a patient. In breast cancer, based on the lack of specific druggable targets, therapy of the triple-negative/basal-like breast cancers (TN/BLBC) subtype is particularly challenging [3].
Besides proteins to which a cancer type or subtype is specifically addicted, there are proteins that are of more general importance for cancer. One of these proteins seems to be the transcription factor Ets1, which is involved in cancer progression in many types of cancers (reviewed in [4], [5]). Ets1 is the founder of the large family of ETS transcription factors, whose members feature a unique DNA binding domain, the ETS domain (reviewed in [6], [7], [8], [9], [10], [11], [12]). The ETS domain is defined by a winged helix-turn-helix structure (wHTH) which recognizes sequences containing a GGAA/T core motif. The ets sequence was orginally found as part of a virally transduced gag/ets/myb fusion gene in the avian erythroblastosis retrovirus E26 and called v(iral)-ets (E26-transformation-specific or E-twenty-six specific sequence) [13], [14]. Later, a human homolog of v-ets, the c(ellular)-ets1 gene coding for Ets1 protein was identified on chromosome 11 [15]. Since then many additional ets genes have been discovered in mammalians, echinoids, nematodes and insects. So far, a total of 28 human ets genes have been described. Besides Ets1, a number of other Ets proteins have been reported to play a role in cancer.
Ets1 is a 54 kDa nuclear protein and primarily acts as a transcriptional activator, though it can also repress gene transcription [16], [17]. Since it is primarily expressed in lymphocytes [18], [19], it plays several critical roles in immunity (reviewed in [20], [21], [22]). In addition, it is important for angiogenesis (reviewed in [23], [24]). Since cells express several Ets proteins at the same time, functional redundancy is possible [25]. This is particularly shown for the so-called housekeeping genes where several Ets factors were found to occupy the proximal promoters in vivo [26]. Also Ras-responsive promoters can be driven through the same Ets/AP1 composite element by different Ets proteins (Ets1 and ERG) [27]. In addition, in murine embryogenesis, Ets1 and the closely related protein Ets2 are similarly able to regulate angiogenesis [28]. Nevertheless, excessive redundancy is prevented by promoter selectivity. First, Ets proteins show sequence preferences for the region flanking the GGAA/T core motif [29], [30], [31], based on which, Ets proteins can be subgrouped into four different classes, where Ets1 belongs to class I and binds preferentially to ACCGGAAGT [31]. Second, Ets proteins show selective cooperative partnerships with other transcription factors (reviewed in [11]). Cooperative partnership may even allow Ets proteins to bind to unfavorable sequences, as was shown for the partnership between Ets1 and Pax5 [32]. Hence, when studying Ets1-specific functions, redundancy among Ets factors has to be considered. It is also important to emphasize that, depending on the cellular context and type of tissue, the function of the Ets1 protein and the mechanism by which its expression and stability is regulated may differ. The aim of this review is to summarize the current knowledge on the functions of Ets1 in carcinoma progression and on the mechanisms by which Ets1 activity is regulated in cancer.
Section snippets
The structure of the human Ets1 protein: domains involved in regulating Ets1 activity
The human full length (fl) Ets1 protein harbors 441 amino acids. Besides the Ets DNA binding domain between aa 331 and 415, it contains the Pointed domain (aa 54–134), the transactivation domain (aa 135–242), the exon VII domain (aa 242–331) and the autoinhibitory module (Fig. 1A). The latter consists of two separated sequences between aa 301 and 330 within the exon VII domain and at the C-terminal end between aa 416 and 441. The Pointed domain is found in a number of Ets proteins, including
Ets1 expression in carcinoma
In a number of carcinoma, including breast, colorectal, endometrial, esophageal, gastric, hepatocellular and lung cancer, higher Ets1 protein or RNA expression in cancer cells of paraffin-embedded formalin-fixed biopsies has been linked to higher grading, poorer differentiation and/or increased invasiveness [188], [189], [190], [191], [192], [193], [194], [195], [196] (Table 1). In addition, increased Ets1 protein levels were found to correlate with higher levels of the invasion-promoting
Conclusions
There is a great body of evidence that Ets1 is critically involved in the progression of almost all carcinomas by being a major driver of key events that take place in advanced cancer. Expressed in cancer cells, Ets1 promotes invasiveness, increases the chance of a cell to undergo EMT and to acquire stem-like features and contributes to the development of drug resistance. Its expression in carcinoma-associated fibroblast further supports invasion of cancer cells by fostering the expression of
Conflict of interest
The author declares that there are no conflicts of interest.
Acknowledgment
The author thanks Angela Dittmer for critically reading the manuscript.
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