# Defining the Critical Function and Regulation of NNMT in Breast Cancer Progression and Metastasis

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2021 · $393,947

## Abstract

N-methyltransferase (NNMT), a key enzyme in the NAD+ salvage pathway with unclear functions, is
expressed highly and specifically in basal-like breast cancer (BLBC). We found that NNMT is robustly
elevated when BLBC cells detach from a matrix and grow in suspension. Knockout (KO) of NNMT not only
inhibits anchorage-independent growth in vitro but also suppresses tumor growth and metastasis in animal
models. Using an unbiased CRISPR-Cas9 library screening, we identified the FOXC1-CARM1 complex as
being responsible for NNMT upregulation in BLBC. Importantly, inhibition of NNMT by either KO or use of an
inhibitor increases the proapoptotic effects mediated by chemo-drugs. We thus hypothesize that NNMT is a
critical gatekeeper that maintains NAD+ homeostasis for BLBC progression and metastasis; this homeostasis
boosts the cellular antioxidative defense machinery, and prevents surges of ROS that BLBC cells encounter
during metastasis. The objective of this proposal is to (1) characterize NNMT function in regulating NAD+
homeostasis in tumor progression and metastasis; (2) delineate the transcriptional regulation of NNMT by
the FOXC1-CARM1 complex; and (3) explore the clinical value of NNMT as a prognostic biomarker and a
druggable target for BLBC. Guided by strong preliminary data, we will test this hypothesis by pursuing three
specific aims: (1) to determine the critical roles of NNMT in BLBC; (2) to delineate NNMT transcription by the
FOXC1-CARM1 complex; and (3) to define the roles of NNMT in the development of mammary gland and
breast cancer metastasis. Our proposal is innovative and significant, because NNMT represents the achilles
heel of BLBC; targeting this metabolic vulnerability offers an effective therapeutic option against metastatic
BLBC.

## Key facts

- **NIH application ID:** 10181998
- **Project number:** 1R01CA259580-01
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Binhua P Zhou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $393,947
- **Award type:** 1
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10181998

## Citation

> US National Institutes of Health, RePORTER application 10181998, Defining the Critical Function and Regulation of NNMT in Breast Cancer Progression and Metastasis (1R01CA259580-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10181998. Licensed CC0.

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