Ets-1 transcription factor is widely expressed in benign and malignant melanocytes and its expression has no significant association with prognosis

Abstract

Ets-1 transcription factor has been associated with tumor progression in various carcinomas, but its expression in malignant melanoma was only recently described. The study was conducted in two steps: exploratory and confirmatory. In the first step, we studied 69 primary melanomas, 28 metastatic melanomas, 10 usual intradermal nevi and 13 various melanocytic skin lesions. In the second step, an additional group of 98 patients with follow-up of up to 200 months was also evaluated. Immunohistochemical analysis of formalinfixed/paraffin-embedded tissues was performed using 1G11 antibody and polymer conjugate for visualization. While Ets-1 was variably expressed in 83% primary melanomas in exploratory and 69% in the confirmatory group, the expression of Ets-1 was also found in normal benign melanocytes and all nevi. Analysis of the exploratory group revealed lower expression of Ets-1 in primary melanomas than in common nevi (P ¼ 0.048, Mann-Whitney U-test) and metastatic melanomas expressed significantly less Ets-1 than primary melanomas (P ¼ 0.015, Mann-Whitney U-test). There was a negative correlation between Ets-1 expression and the largest dimension of the primary tumors (r ¼ 0.23, P ¼ 0.034, Spearman's correlation rank test), but no correlation with the depth of tumor invasion (Breslow thickness) or the presence of ulceration was found. Analyses of the confirmatory group revealed no association between Ets-1 expression with disease-specific survival or time to treatment failure. However, a statistical trend was found for worse outcome for those primary melanomas that had strong expression (H-score 4100) of Ets-1 (P ¼ 0.054). Ets-1 is expressed in benign melanocytes probably due to their neural crest origin. We conclude that Ets-1 expression cannot be used to differentiate between benign and malignant melanocytic lesions and it has no definite association with clinical outcome. At the same time, its role in tumor progression in some cases of malignant melanoma cannot be entirely excluded. Keywords: Ets-1; malignant melanoma; survival; neural crest Malignant melanoma originates from melanocytes derived from the neural crest. 1 It is the most deadly form of skin cancer, whose incidence is rapidly increasing worldwide. 2 To date the most reliable prognostic marker of malignant melanoma is the vertical thickness (Breslow thickness) of the primary tumor. 3,4 Although progression of malignant melanoma occurs through a series of well-defined steps, the knowledge of genetic and phenotypic background for the disease is still rather scarce. The proto-oncogene ETS-1 belongs to the ETS family of transcription factors that also include, among others, ets-2, elf-1, fli-1 and PU-1. 5-7 Ets-1 plays an important role in cancer progression due to its ability to activate transcription of metastasis-, angiogenesis-and invasion-associated genes. [8][9][10][11][12] In a limited study on 10 melanomas and 24 benign melanocytic lesions, Keehn et al 13 recently reported expression of the Ets-1 in melanocytic lesions and suggested that E...

Ets-1 mediates upregulation of Mcl-1 downstream of XBP-1 in human melanoma cells upon ER stress

“…In melanoma, the levels Ets-1 were similarly found to be higher than those in benign melanocytic lesions and melanocytes, and to increase with progression of the disease (Poser and Bosserhoff, 2004; Rothhammer et al , 2004; Torlakovic et al , 2004). Consistently, the results in this study also showed that Ets-1 was commonly expressed at high levels in fresh melanoma isolates.…”

“…Increased Ets-1 expression has been reported to correlate with grade of malignancy and poorer prognosis in a number of cancers (Davidson et al , 2001; Span et al , 2002). In melanoma, high levels of Ets-1 are often associated with progression of the disease (Poser and Bosserhoff, 2004; Rothhammer et al , 2004; Torlakovic et al , 2004). The role of Ets-1 in regulation of apoptosis seems to be cell type-dependent, as it protects against apoptosis in some cell types, but induces apoptosis in others (Bories et al , 1995; Sato et al , 2001; Teruyama et al , 2001; Dittmer, 2003).…”

Constitutive activation of the ETS‐1‐miR‐222 circuitry in metastatic melanoma

“…ETS‐1 is expressed in melanocytes migrating from the neural crest during embryogenesis and in normal adult melanocytes, but its role in malignant melanomas appears controversial. ETS‐1 has been reported either as a valuable diagnostic/prognostic marker (Rothhammer et al., 2004) or as molecule with no clear association with clinical outcome (Torlakovic et al., 2004).…”

Adaptation to ER Stress as a Mechanism of Resistance of Melanoma to Treatment

“…Ets-1 is expressed at high levels in many types of cancers and is involved in many biological processes in cancer cells such as cell growth and survival (Davidson, et al, 2001;Span, et al, 2002). In melanoma, the levels Ets-1 were similarly found to be higher than those in benign melanocytic lesions and melanocytes and to increase with progression of the disease (Rothhammer, et al, 2004;Torlakovic, et al, 2004). Although the role of Ets-1 in regulation of apoptosis may vary between different cell types, transcriptional up-regulation of Mcl-1 by Ets-1 in melanoma cells subjected to ER stress indicates that it is critical in protection of melanoma cells against ER stress-induced apoptosis (Dong, et al, 2011).…”