# Glycolytic signaling of p38gamma in breast cancer

> **NIH VA I01** · CLEMENT J. ZABLOCKI VA MEDICAL CENTER · 2024 · —

## Abstract

Triple-negative breast cancer (TNBC) does not express estrogen receptor (ER), progesterone receptor (PR)
and Her2 as therapeutic targets and consequently has the worst prognosis among all types of breast cancers.
Metabolic reprogramming toward aerobic glycolysis (also called the Warburg effect) is a hallmark of cancer,
which is further activated in TNBC. Although aerobic glycolysis may be therapeutically targeted, the druggable
pathway has not been identified. p38 is a TNBC oncogene and stimulates glucose uptake and metabolic
adaption. This proposal will test the hypothesis that p38 promotes TNBC oncogenesis by stimulating
PFKFB3/GLUT1-dependent aerobic glycolysis.
 This hypothesis is based on the following findings: 1) p38 stimulates glucose transporter 1 (GLUT1)
expression and increases glucose uptake; 2) p38 promotes TNBC oncogenesis; 3) TNBCs are highly
glycolytic with elevated PFKFB3 and GLUT1 expression; 4) p38 binds PFKFB3, a key glycolytic activator, in
TNBC cells, whereas it interacts with much less glycolytic three family members (PFKFB1, 2 and 4) in non-
TNBC cells; 5) MS/MS analysis identifies that p38 phosphorylates PFKFB3 at S467 leading to its stabilization,
whereas data from public data-base shows that p38 gene expression is correlated with GLUT1 in invasive
breast cancer tissues; 6) conditional p38 knockout (KO) inhibits tumorigenesis in a TNBC-like PyMT mouse
genetic breast cancer model and decreases PFKFB3/GLUT1 expression; 7) p38 overexpression in TNBC
cells increases PFKFB3/GLUT1 abundance, promotes their interaction, and stimulates ECAR (an indicator of
glycolysis), indicating its activity of stimulating aerobic glycolysis by forming a ternary complex; and 8)
pharmacological p38 and PFKFB3 inhibitors cooperatively decrease p-PFKFB3/PFKFB3/GLUT1 levels and
inhibit TNBC growth in a manner dependent on p38. These results together indicate that p38 links
aerobic glycolysis and TNBC oncogenesis through activating PFKFB3 and GLUT1.
 We will test this hypothesis by targeting the following aims: AIM 1 will investigate if p38 links aerobic
glycolysis and TNBC oncogenesis through interaction with PFKFB3 and stimulating of PFKFB3
phosphorylation at S467; AIM 2 will determine if p38 cooperates with both PFKFB3 and GLUT1 to promote
aerobic glycolysis and TNBC oncogenesis by stimulating a S467-dependent ternary-complex; and AIM 3 will
determine if the p38-PFKFB3 kinase cascade is a therapeutic target for TNBC and if the p38/PFKFB3/Glut1
co-upregulation with elevated p-PFKFB3 identifies a subgroup of TNBC with a worse prognosis in clinic. These
studies will demonstrate if the p38-PFKFB3 kinase cascade is a novel therapeutic target for TNBC and reveal
if a combined application of p38/PFKFB3 pharmacological inhibitors is a potential effective therapeutic
strategy that will impact TNBC clinical outcome and veteran health care.

## Key facts

- **NIH application ID:** 10871806
- **Project number:** 5I01BX005066-04
- **Recipient organization:** CLEMENT J. ZABLOCKI VA MEDICAL CENTER
- **Principal Investigator:** GUAN CHEN
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2021-04-01 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10871806

## Citation

> US National Institutes of Health, RePORTER application 10871806, Glycolytic signaling of p38gamma in breast cancer (5I01BX005066-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10871806. Licensed CC0.

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