The Binomial “Inflammation-Epigenetics” in Breast Cancer Progression and Bone Metastasis: IL-1β Actions Are Influenced by TET Inhibitor in MCF-7 Cell Line

Abstract

The existence of a tight relationship between inflammation and epigenetics that in primary breast tumor cells can lead to tumor progression and the formation of bone metastases was investigated. It was highlighted how the induction of tumor progression and bone metastasis by Interleukin-1 beta, in a non-metastatic breast cancer cell line, MCF-7, was dependent on the de-methylating actions of ten-eleven translocation proteins (TETs). In fact, the inhibition of their activity by the Bobcat339 molecule, an inhibitor of TET enzymes, determined on the one hand, the modulation of the epithelial-mesenchymal transition process, and on the other hand, the reduction in the expression of markers of bone metastasis, indicating that the epigenetic action of TETs is a prerequisite for IL-1β-dependent tumor progression and bone metastasis formation.

The prognostic value of absolute lymphocyte count and neutrophil‐to‐lymphocyte ratio for patients with metastatic breast cancer: a systematic review and meta‐analysis

“…As an important indicator of inflammatory immunity, the number of neutrophils and lymphocytes can affect the proliferation, angiogenesis, and distant metastasis of tumor cells by secreting related cytokines and chemokines ( 54 ). IL-1β ( 61 ), IL-6 ( 62 ), IL-10 ( 63 ), etc. not only lead to epigenetic modifications (methylation of DNA) but also promote the activation of epithelial–mesenchymal transition (EMT), tumor cell homing, and positive feedback amplification of the protumorigenic inflammatory loop between tumor and resident cells ( 64 ).…”

Epigenetic control of the vicious cycle

“…Expression of IL-1β in MCF7 human breast cancer cells increases tumor progression and depends on the demethylating actions of ten-eleven translocation proteins (TETs). Inhibition of TET enzymes interfere with EMT and reduce markers of bone metastasis including versican, osteopontin, and prolactin receptor [10] . These studies highlight the role of DNA hypomethylation as an essential regulator of oncogene expression in bone metastatic breast cancer and suggest that inhibiting DNA hypomethylation may be a therapeutic strategy to reduce bone metastasis.…”

“…NCT00359606 is a phase I trial using intravenous 5-fluoro-2′-deoxycytidine (5-fluoro-2-deoxycytidine) (FdCyd), a DNA methyltransferase inhibitor, paired with the cytidine deaminase inhibitor tetrahydrouridine (THU). Given previous findings highlighting the important role of DNA hypermethylation in metastasis and tumor progression [4] , [5] , [6] , [7] , [8] , [9] , [10] , investigators hypothesized that FdCyd would be more successful at treating advanced solid tumors, including metastatic breast cancer, than THU alone. However, recent studies highlight the role of DNA hypomethylation in elevated expression of oncogenes associated with bone metastasis [9] , [10] .…”

“…Given previous findings highlighting the important role of DNA hypermethylation in metastasis and tumor progression [4] , [5] , [6] , [7] , [8] , [9] , [10] , investigators hypothesized that FdCyd would be more successful at treating advanced solid tumors, including metastatic breast cancer, than THU alone. However, recent studies highlight the role of DNA hypomethylation in elevated expression of oncogenes associated with bone metastasis [9] , [10] . Thus, it will be essential to closely monitor patients receiving DNMT inhibitors such as FdCyd to ensure that inhibition of DNMTs does not induce hypomethylation of pro-metastatic oncogenes that result in progression of bone metastatic breast cancer.…”

“…When designing clinical trials involving epigenetic regulators, it is important to consider findings from pre-clinical studies. For example, the use of DNMT inhibitors like FyCyd is currently in clinical trials for the treatment of advanced breast cancer (NCT00359606), but this may cause hypomethylation resulting in the expression of oncogenes, similar to TET enzymes that induce tumor proliferation [10] . Additionally, pre-clinical studies suggest that HDAC inhibition may have a clinical benefit in bone metastatic breast cancer if patients receive a bisphosphonate to reduce bone resorption.…”