TLR4/IFNγ pathways induce tumor regression via NOS II-dependent NO and ROS production in murine breast cancer models.

Toll-like receptor (TLR) 4 agonists have emerged as a new group of molecules used for cancer therapy. They have been exploited to enhance the immunogenicity of current chemotherapeutic regimens. However, their effects on cancer cells remain elusive.

[To stimulate or to inhibit nitric oxide production in mammary tumors?].

NO is a molecule produced in different amounts by two types of enzymes, constitutive NO-synthases and inducible NO-synthase, the last one produce large amount of NO. In tumor outcome, its role may be either beneficial or detrimental due to its actions in the different steps of tumor growth and metastasis. This review deals with mammary tumors and the mechanisms lying behind NO effects.

Tumour-derived and host-derived nitric oxide differentially regulate breast carcinoma metastasis to the lungs.

To study the role of nitric oxide (NO) in lung metastasis of breast carcinoma, we isolated two cell clones (H and J) from the parental EMT-6 murine breast carcinoma cell line, based on their differential NO production. In vitro, EMT-6 J cells, but not EMT-6H cells, constitutively expressed inducible NO synthase (NOS II) and secreted high levels of NO. IL-1beta increased NO production in both clones, and TNF-alpha had a synergistic effect on IL-1beta-induced NO production, but NO production by EMT-6 J cells was always higher than by EMT-6H cells.

Casein kinase II-mediated phosphorylation of NF-kappaB p65 subunit enhances inducible nitric-oxide synthase gene transcription in vivo.

Nitric oxide (NO) produced by inducible nitric-oxide synthase (NOSII) is mainly regulated at the transcriptional level by the nuclear factor-kappaB (NF-kappaB). In the present study, we further analyzed the role of NF-kappaB in the in vivo transcriptional regulation of NOSII gene by comparing two clones isolated from the EMT-6 mouse mammary cancer cell line. In response to interleukin (IL)-1beta or lipopolysaccharide (LPS), EMT-6 clone J (EMT-6J) cells produce 3-fold more NO than EMT-6 clone H (EMT-6H) cells, an effect correlated with enhanced activation of NF-kappaB in EMT-6J cells.