# Regulation of Mammary Gland Development by Sirtuin 4

> **NIH NIH SC2** · SAN JOSE STATE UNIVERSITY · 2022 · $146,500

## Abstract

Project Summary
The mitochondrial enzyme sirtuin 4 (SIRT4) is downregulated in breast cancer tissue, but the reason for this is
not clear. In order to elucidate this, we first sought to determine the role of SIRT4 in normal mammary tissue.
We have discovered that SIRT4 is critical for ensuring normal mammary development. In mice with a total lack
of SIRT4 (SIRT4KO mice), mammary glands do not fully develop during puberty. As a result, they do not produce
enough maternal breast milk during pregnancy and nearly 100% of their young perish two days after birth. We
now seek to uncover the mechanism by which SIRT4 influences mammary gland development. First, we seek
to investigate the potential role of the ovarian hormones 17β-estradiol (E2) and progesterone (P4) in mediating
the effects of SIRT4 on mammary development (Aim 1). These two hormones are essential for initiating growth
of milk-producing mammary ducts during puberty and pregnancy and the mammary defects seen in SIRT4KO
mice are reminiscent of the defects seen in mice with disrupted E2 or P4 signaling. Furthermore, since SIRT4 is
found in mitochondria and is known to have many metabolic effects, we seek to investigate the possibility that
SIRT4 regulates mammary development by controlling nutrient metabolism in mammary glands (Aim 2). Altered
metabolic states in both mice and humans have been shown to inhibit mammary development. For example,
both underweight and overweight mice have impaired mammary development that can result in insufficient
lactation. Thus, we seek to determine whether the known effects of SIRT4 on nutrient metabolism may contribute
to how SIRT4 regulates mammary development. Overall, our proposed studies will reveal a new role for SIRT4
in regulating mammary development. Ultimately, by investigating how SIRT4 influences normal mammary
physiology, we may better understand why SIRT4 expression levels are downregulated in breast cancer tissue
and whether this contributes to disease progression.

## Key facts

- **NIH application ID:** 10377410
- **Project number:** 5SC2GM141997-02
- **Recipient organization:** SAN JOSE STATE UNIVERSITY
- **Principal Investigator:** FRANK KHAN HUYNH
- **Activity code:** SC2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $146,500
- **Award type:** 5
- **Project period:** 2021-04-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10377410

## Citation

> US National Institutes of Health, RePORTER application 10377410, Regulation of Mammary Gland Development by Sirtuin 4 (5SC2GM141997-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10377410. Licensed CC0.

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