Role of TET1 and 5hmC in an obesity-linked pathway driving cancer stem cells in triple-negative breast cancer

Triple negative breast cancer (TNBC) is a subtype of breast cancer that lacks expression of estrogen receptor, progesterone receptor and the epidermal growth factor receptor 2 (HER2) but is enriched with cancer stem cell-like cells (CSCs). 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 (5mC) by action of tet methylcytosine dioxygenase enzymes (e.g., TET1); and while 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 (H2O2)-dependent activation of a novel gene expression cascade driving self-renewal and expansion of CSCs in TNBC. Evidence presented also supports that the H2O2 impacting this pathway arises due to endogenous mechanisms - including down-regulation 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 H2O2 and linked to obesity-driven TNBC tumor-initiating CSCs; thus, it provides new understanding that may advance TNBC prevention and treatment strategies.