# Mechanisms that impact metastatic progression of triple negative breast cancer

> **NIH VA I01** · BIRMINGHAM VA MEDICAL CENTER · 2022 · —

## Abstract

There is a notably high incidence of breast cancer among younger military women (20% to 40% higher).
The incident rate of breast cancer for active duty women is seven times higher than the average incident
rate of fifteen other cancer types across all service members. An estimated 90% of deaths due to breast
cancer are a consequence of metastatic disease. Thus, metastasis is a formidable and clearly an unmet
challenge. We identified that NMI (N-Myc Interactor) protein is undetectable in more than 60% of primary
breast tumors that had undergone metastatic dissemination. To recapitulate this clinical scenario, we
generated a mammary specific-NMI knockout (Nmi-KO) mouse. In this model, we deciphered that loss of
NMI allows for unrestrained signaling through the Wnt/β-catenin pathway and enables mesenchymal
transition (EMT) of mammary tumors cells leading to increased metastasis. We found that NMI protein loss
is observed predominantly in triple negative breast cancers (TNBC). TNBC is inherently highly invasive and
metastatic and is recognized for aberrantly activated Wnt/β-catenin signaling. While investigating cellular
adaptations of TNBC to low doses of a Wnt/β-catenin inhibitor, iCRT14, we observed that iCRT14 clearly
decreased the number of nucleoli per TNBC cell.
The nucleolus is the primary site of ribosomal RNAs (rRNA) synthesis and assembly with ribosomal
proteins. It is a vital component in the ability of a cancer cell to meet the dynamic metabolic demands of
tumor progression. Classical pathologic diagnosis of tumor tissue has revealed that nucleolar hypertrophy
and increased nucleolar number are predictive and prognostic parameters of increased mortality. Our
observations reveal that TNBCs show increased number of nucleoli per cell compared to non-TNBC
specimens. Despite the importance of Wnt/β-catenin signaling, there is a clear gap in knowledge about the
relevance of this pathway to nucleolar functions, specifically in TNBCs. We hypothesize that TNBCs are
`addicted to' elevated ribosome biogenesis. Our proposed investigations are designed to test if inhibition of
Wnt/β-catenin signaling will be an effective approach to disable ribosome biogenesis of TNBCs, specifically
in those that lack NMI expression.
While Wnt/β-catenin signaling has been one of the major factors driving TNBC metastases, therapeutic
strategies are still evolving. Our research efforts will advance this field and unravel critical information that
identifies the novel drug targets. Overall our efforts are congruent with the mission of the VA women's
health initiative.

## Key facts

- **NIH application ID:** 10347166
- **Project number:** 5I01BX003374-06
- **Recipient organization:** BIRMINGHAM VA MEDICAL CENTER
- **Principal Investigator:** Rajeev S Samant
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10347166

## Citation

> US National Institutes of Health, RePORTER application 10347166, Mechanisms that impact metastatic progression of triple negative breast cancer (5I01BX003374-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10347166. Licensed CC0.

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