# NNMT regulation of m6A RNA modification in TNBC progression

> **NIH NIH R21** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $179,992

## Abstract

PROJECT/SUMMARY ABSTRACT
Early-stage triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype in which, despite
standard of care, approximately 1 in 3 patients relapse within the first three years of diagnosis. Through our
group’s previous identification of the glucocorticoid receptor (GR) signaling pathway as a risk factor for
recurrence in TNBC, we discovered that the gene encoding nicotinamide N-methyltransferase (NNMT) is a
direct GR transcriptional target. We also found that high NNMT expression, independently of GR expression, is
associated with a significantly worse outcome in early-stage chemotherapy-treated TNBC, suggesting a role
for high NNMT activity in tumor cell chemotherapy-resistance and metastasis. Recently, accumulating
evidence suggests that NNMT activity may play a role in the biology of various human cancers; however,
NNMT’s mechanism of action in TNBC is completely unknown. Based on our preliminary data suggesting that
NNMT activity induces hypomethylation of an important subset of TNBC mRNAs, we hypothesize that NNMT
alters an oncogenic epitranscriptome of aggressive TNBC. Our central hypothesis is that high NNMT activity
promotes TNBC cell survival and metastasis by reducing m6A mRNA modification of target transcripts,
increasing oncogenic mRNA stability, and upregulating resultant cell survival and metastatic protein
expression. In Aim 1, we will determine whether NNMT depletion or inhibiting NNMT activity biochemically
alters m6A mRNA modification. We will also determine whether high versus depleted NNMT-expressing TNBC
cells exhibit differential motility/invasion, adherence-independent viability and protection from chemotherapy-
induced apoptosis in two dimensional (in vitro) assays. In Aim 2, using control, NNMT-knockdown, and NNMT-
overexpression-rescue TNBC xenografted cells and a syngeneic model, we will determine whether NNMT
expression/activity contributes to altered expression of m6A mRNA modified tumor-promoting genes and
increases tumor regrowth. The same experiments will also be performed with and without NNMT inhibitor
treatment. In summary, NNMT is a putative driver of epitranscriptomic mRNA modification that we will test as a
driver of chemoresistance and metastatic gene expression and will test as a novel therapeutic target in TNBC.

## Key facts

- **NIH application ID:** 9880417
- **Project number:** 7R21CA239048-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Suzanne Daniela Conzen
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $179,992
- **Award type:** 7
- **Project period:** 2019-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9880417

## Citation

> US National Institutes of Health, RePORTER application 9880417, NNMT regulation of m6A RNA modification in TNBC progression (7R21CA239048-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9880417. Licensed CC0.

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