# MNSOD ACETYLATION PROMOTES CANCER STEM CELL PHENOTYPES IN BREAST CANCER

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $352,274

## Abstract

PROJECT SUMMARY / ABSTRACT:
Cancer stem cells are a rare and yet critically important subpopulation of cells in tumors
associated with treatment failure and metastatic recurrence. Though it is becoming increasingly
clear that targeting this subpopulation could lead to therapies with better odds of a cure it is still
unknown how these cells originate and what are the biochemical processes that promote
“stemness” in cancer. Our laboratory found that alterations in the metabolism of mitochondrial
reactive oxygen species (ROS) promote aberrant activation of hypoxia-induced factor 2α
(HIF2α). The activation of HIF2α is a well-established mechanism of stemness that has also
been implicated in metastatic recurrence as well as treatment failure in women with breast
cancer. We found that a posttranslational modification (i.e. acetylation) of a primary enzyme
involved in the metabolism of mitochondrial ROS, manganese superoxide dismutase (MnSOD)
breaks the tetrameric structure that has antioxidant function turning the enzyme into a monomer
that promotes ROS formation and activates HIF2α. We also found that MnSOD-K68Ac
accumulates prominently in breast cancers expressing low estrogen receptor levels. Hence, it is
proposed that MnSOD has a dichotomous behavior functioning as a suppressor of tumor
initiation (antioxidant function) and yet promotes cancer stem cell reprogramming later on in
established tumors. This proposition is supported by the finding of strong associations between
a MnSOD/HIF2α signature present in metastatic lesions compared to primary tumor samples
from the same breast cancer patients. Hence, this application aims at determining: (1) if
MnSOD-Ac reprograms tumor cells to stem-like phenotypes associated with chemoresistance.
(2) if the biochemical and/or genetic targeting of MnSOD-Ac or HIF2α in established tumors of
mice with the MnSODhigh/HIF2α signature (MMTV.PyVT) suppresses chemoresistance and/or
metastasis. (3) if there is an association between subsets of women with breast cancer that
exhibit a MnSODhigh or MnSOD-Ac, or MnSOD-ROS-HIF2α molecular axis signature and
develop chemoresistance or have increased risk of metastatic recurrence.

## Key facts

- **NIH application ID:** 10193167
- **Project number:** 7R01CA216882-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Marcelo G. Bonini
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $352,274
- **Award type:** 7
- **Project period:** 2018-08-14 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10193167

## Citation

> US National Institutes of Health, RePORTER application 10193167, MNSOD ACETYLATION PROMOTES CANCER STEM CELL PHENOTYPES IN BREAST CANCER (7R01CA216882-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10193167. Licensed CC0.

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