# The role of NRF2 in breast cancer dormancy and recurrence

> **NIH NIH F31** · DUKE UNIVERSITY · 2020 · $37,307

## Abstract

PROJECT SUMMARY
 Over half of breast cancer deaths occur later than 5 years after initial diagnosis and treatment. In these
cases of recurrent breast cancer, patients have no detectable tumor burden following treatment, suggesting that
a small population of malignant cells is able to survive therapy and remain dormant for years. Despite the high
risk of recurrence in breast cancer, the cellular properties of cancer cells that evade therapy and survive in a
dormant state are largely uncharacterized. In particular, the metabolic requirements of dormant and recurrent
tumor cells remain unknown. To address this, our lab uses a transgenic mouse model that recapitulates many
of the features of dormancy and recurrence in breast cancer. In this model, doxycycline administration to
bitransgenic MMTV-rtTA;TetO-Her2 (MTB/TAN) mice leads to Her2 expression and the formation of invasive
mammary adenocarcinomas. Removal of doxycycline causes Her2 down-regulation and induces tumor
regression. However, a small population of cells persists in a dormant state before eventually re-initiating
proliferation to form a recurrent tumor. I have used this model to generate in vitro cultures, and I can study the
process of tumor dormancy and recurrence both in vivo and in vitro. In preliminary studies, I have shown that
Her2 inhibition leads to profound metabolic changes accompanied by the generation of reactive oxygen species
(ROS). The master transcription factor that mediates the cellular antioxidant response, NRF2, becomes activated
following Her2 inhibition, and recurrent tumors exhibit persistent NRF2 activation. NRF2 has well documented
oncogenic roles in lung and liver cancers, but a functional role for its activation following anti-Her2 therapy
remains uncharacterized. However, antioxidants can rescue cell death following Her2 inhibition, suggesting that
cells which deploy a robust NRF2-regulated antioxidant response may preferentially survive following Her2
inhibition. Based upon these preliminary data, I propose to characterize the functional effects and mechanistic
basis of oxidative stress and NRF2 activation during tumor regression, dormancy and recurrence.

## Key facts

- **NIH application ID:** 9843438
- **Project number:** 5F31CA228321-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Douglas Fox
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $37,307
- **Award type:** 5
- **Project period:** 2019-01-01 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9843438

## Citation

> US National Institutes of Health, RePORTER application 9843438, The role of NRF2 in breast cancer dormancy and recurrence (5F31CA228321-02). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/9843438. Licensed CC0.

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