The dysregulation of mitochondrial networks responsible for maintaining normal metabolism is an
established hallmark of cancer and an early event in tumorigenesis. The disruption of cell metabolism
leads to accumulation of reactive oxygen species (ROS) and triggers maladaptive signaling that
disrupts metabolic balance, which can establish a tumorigenic and/or therapy resistant phenotype.
In this regard, a subgroup of estrogen receptor-positive (ER+) breast malignancies, which exhibit
increased ROS levels and a high risk of recurrence due to endocrine therapy, has been identified.
We recently found a novel mitochondrial signaling axis centered on manganese superoxide
dismutase (MnSOD), which when the acetylation (Ac) status of lysine 68 (K68-Ac) is altered, disrupts
cell metabolism, leading to aberrant ROS levels (Zhu, Nature Commun., 2019). In addition, breast
cancer cells expressing a MnSOD-K68-Ac mimic mutant (MnSODK68Q) exhibited increased HIF2a
(known to promote stemness-like properties), increased SOX2 and Oct4 (two established stem cell
biomarkers), leading to oncogenicity and pan resistance phenotype (PanR) to agents commonly
used in luminal B breast malignancies-implying that disruption of cell metabolism reprograms tumors
to exhibit a lineage plasticity phenotype. Based on our new data, our recent publication (Zhu et al,
Nature Commun. 2019), and work by others, it is hypothesized that dysregulated MnSOD biology,
due to aberrant/increased MnSOD-K68-Ac levels, disrupts normal cellular and mitochondrial
metabolism. This initiates metabolic reprogramming, via increased levels of HIF2a, leading to a cell
stemness-mediated tumor-permissive and/or PanR phenotype. Thus, we seek to further explore how
MnSOD-K68-Ac disrupts cell metabolism and promotes a stemness-like phenotype, leading to
oncogenicity and/or PanR. Finally, will GC4419 exposure, a chemical SOD detoxification mimic,
reverse the oncogenic and/or PanR phenotypes?