# The role of phosphorylation of isocitrate dehydrogenase in breast cancer

> **NIH NIH P20** · UNIVERSITY OF ARKANSAS AT FAYETTEVILLE · 2021 · $225,000

## Abstract

Project Summary – Project Leader Chenguang Fan
Breast cancer is one of the top threats to women’s health. About 1 in 8 US women (~12%) will develop invasive
breast cancer over the course of her lifetime. Previous studies have shown the important role of a key
tricarboxylic acid cycle (TCA) enzyme isocitrate dehydrogenase (IDH) in breast cancer. A variety of IDH
alternations including somatic mutations, aberrant expression, and altered activities have been observed in
breast cancer patients. Recently, phosphoproteomic studies of breast cancer cells have identified several unique
phosphorylation sites in IDH isoforms, and those sites are specific for different types of breast cancer. Such
heterogeneity poses challenges for effective diagnosis and treatment, so there is a critical need to discover
specific mechanisms of IDH phosphorylation for breast cancer. The overall goal of this project is to identify the
role of IDH phosphorylation in breast cancer. As IDH homologues in bacteria are known to be regulated by
phosphorylation, the hypothesis is that phosphorylation of IDH in human cells alters IDH functions and cellular
metabolism, thus facilitating cancerous transformations. To test this hypothesis, three specific aims are proposed:
Aim 1 is to identify the effects of phosphorylation on IDH enzyme functions at the molecular level. Aim 2 is to
identify the influences of IDH phosphorylation on cellular metabolism and redox status at the metabolic level.
Aim 3 is to identify mechanisms or pathways in which IDH phosphorylation plays roles in breast cancer at the
cellular level. The oncogenic transformation test on normal human mammary epithelial cells will be performed to
identify whether IDH phosphorylation is an initiator for breast cancer or a cellular adaption to facilitate cancer
formation. This proposal is innovative because: 1) the functions of IDH phosphorylation in human remain largely
unknown, and this proposal will be the first to systematically study the phosphorylation of all the three IDH
isoforms in human cells; 2) To address the problem that the classic glutamate-substitution method for
phosphorylation studies is not always effective, the genetic code expansion technique will be applied in this
proposal to co-translationally incorporate phosphoamino acid (pAA) at a controlled site in target proteins in order
to produce site-specifically phosphorylated IDH variants which have been identified in breast cancer. This
proposal will be the first to introduce pAA-incorporation systems into human cell lines to study phosphorylation
in living cells. The proposed research is significant because it will provide key evidence for the influences and
roles of IDH phosphorylation in breast cancer. Given that protein phosphorylation is usually involved in signaling
pathways through different kinase cascades, the role of IDH phosphorylation in breast cancer could be different
from other IDH alternations. Ultimately, the proposed studies on IDH phosphor...

## Key facts

- **NIH application ID:** 10090749
- **Project number:** 1P20GM139768-01
- **Recipient organization:** UNIVERSITY OF ARKANSAS AT FAYETTEVILLE
- **Principal Investigator:** Chenguang Fan
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $225,000
- **Award type:** 1
- **Project period:** 2021-04-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10090749

## Citation

> US National Institutes of Health, RePORTER application 10090749, The role of phosphorylation of isocitrate dehydrogenase in breast cancer (1P20GM139768-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10090749. Licensed CC0.

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