EZH2 overexpression occurs in various malignancies and is associated with a poor outcome. We have so far demonstrated that EZH2 downregulates the important genes such as E-cadherin and RUNX3 by increasing histone H3K27 trimethylation. However, the mechanism of EZH2 overexpression in various cancer cells remains unclear. In this study we carried out a promoter analysis of the EZH2 gene and investigated whether a survival signal that is upregulated in cancer cells is related to overexpression at the transcription level. We also explored the clinical relevance of the signaling pathway that leads to EZH2 overexpression in breast cancer and demonstrated that MEK-ERK1/2-Elk-1 pathway leads to EZH2 overexpression. The triple-negative and ERBB2-overexpressing subtypes of breast cancer are known to contain more rapidly proliferating breast cancer cells. The signaling pathway connected to EZH2 overexpression was associated with both aggressive subtypes of breast cancer. We show the significance that overexpression of histone modifier protein EZH2 in cancer cells and our study could pave the way for EZH2 inhibition to become an efficient treatment for more aggressive breast cancers.

Recently, an association between tumor infiltrating Forkhead box P3 regulatory T cells (T reg ) and an unfavorable prognosis has been clinically shown in some cancers, but the mechanism of T reg induction in the tumor microenvironment remains uncertain. The aims of the present study were to examine the relationship between T reg and patient outcome and to investigate whether T reg induction is influenced by the characteristics of cancer-associated fibroblasts (CAF) in lung adenocarcinoma. The numbers of T reg in both the tumor stroma and the tumor nest were counted in 200 consecutive pathological stage I lung invasive adenocarcinoma specimens. To examine whether the characteristics of CAF influence T reg induction, we selected and cultured CAF from low T reg and high T reg adenocarcinoma. The number of T reg was much higher in the stroma than in the nest (P < 0.01). Patients with high T reg had a significantly poorer prognosis than those with low T reg (overall survival: P = 0.03; recurrence-free survival: P = 0.02; 5-year overall survival: 85.4% vs 93.0%). Compared with the CAF from low T reg adenocarcinoma, culture supernatant of the CAF from high T reg adenocarcinoma induced more T reg (P = 0.01). Also, CAF from high T reg adenocarcinoma expressed significantly higher mRNA levels of transforming growth factor-b (P = 0.01) and vascular endothelial growth factor (P = 0.01), both of which are involved in T reg induction. Our studies suggest the possibility that CAF expressing immunoregulatory cytokines may induce T reg in the stroma, creating a tumor-promoting microenvironment in lung adenocarcinoma that leads to a poor outcome. (Cancer Sci 2013; 104: 409-415)

CD204 (+) TAMs were an independent prognostic factor in lung squamous cell carcinoma. CD204 (+) TAMs, along with other tumor-promoting stromal cells such as regulatory T cells and endothelial cells, may create tumor-promoting microenvironments.

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