Role of TET1 and 5hmC in an Obesity-Linked Pathway Driving Cancer Stem Cells in Triple-Negative Breast Cancer

Abstract

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that lacks expression of estrogen receptor, progesterone receptor, and the HER2 but is enriched with cancer stem celllike cells (CSC). CSCs are the fraction of cancer cells recognized as the source of primary malignant tumors that also give rise to metastatic recurrence. 5-Hydroxymethylcytosine (5hmC) is a DNA epigenetic feature derived from 5-methylcytosine by action of tet methylcytosine dioxygenase enzymes (e.g., TET1); and although TET1 and 5hmC are required to maintain embryonic stem cells, the mechanism and role in CSCs remain unknown. Data presented in this report support the conclusion that TET1 and TET1-dependent 5hmC mediate hydrogen peroxide (H 2 O 2 )-dependent activation of a novel gene expression cascade driving self-renewal and expansion of CSCs in TNBC. Evidence presented also supports that the H 2 O 2 affecting this pathway arises due to endogenous mechanismsincluding downregulation of antioxidant enzyme catalase in TNBC cells-and by exogenous routes, such as systemic inflammation and oxidative stress coupled with obesity, a known risk factor for TNBC incidence and recurrence.Implications: This study elucidates a pathway dependent on H 2 O 2 and linked to obesity-driven TNBC tumor-initiating CSCs; thus, it provides new understanding that may advance TNBC prevention and treatment strategies.

Advances in the DNA methylation hydroxylase TET1

“…This study opens a new avenue for TNBC treatment by targeting the EZH2-H3K27me3-TET1 pathway, which can modulate the epigenetic landscape. In 2020, Bin Bao et al [ 51 ] demonstrated that TET1- and TET1-dependent 5hmC mediated a novel hydrogen peroxide-(H 2 O 2 )-dependent gene expression cascade response driving the self-renewal and expansion of cancer stem cell-like cells (CSCs) in TNBC.…”

Epigenetic Regulation of Breast Cancer Stem Cells Contributing to Carcinogenesis and Therapeutic Implications

“…Subsequently, methyl-CpG-binding domain protein 2, variant 2 (MBD2_v2), is activated, and finally maintains CSC self-renewal. Furthermore, obesity increases levels of pro-inflammatory signaling factors, such as cytokines, which increase the H 2 O 2 level in breast cancer cells [ 155 ].…”

The Roles of DNA Demethylases in Triple-Negative Breast Cancer

“…TET1 expression was demonstrated to promote cell metastasis in colorectal cancer and activation of PI3K oncogenic signaling in TNBC. TET1 expression was shown to correlate with cell migration, cancer stemness tumorigenicity, and poor survivals in epithelial ovarian cancer and in TNBCs [ 77 , 78 , 79 ].…”

“…In another study that supports the oncogenic role of TET1, it was shown that TET1-mediated hypomethylation upregulated gene expressions that drove self-renewal and expansion of cancer stem cells in TNBC. This TET1-mediated oncogenic function is an alternate mechanism that was shown to be due to the downregulation of the catalase enzyme which increases the hydrogen peroxide levels, or be due to exogenous routes such as systemic inflammation and oxidative stress within the context of obesity in TNBC [ 77 ].…”