# Elucidating the Mechanisms by which Hexokinase 2 Regulates Breast Cancer Metastasis

> **NIH NIH F30** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2020 · $50,520

## Abstract

Project Summary:
Despite large improvements in breast cancer therapy, toxic side effects from chemotherapy are a major
limitation; thus, it is necessary to develop novel therapeutic strategies that specifically target cancer cells while
sparing healthy cells. One hallmark of cancer cells is the “Warburg Effect,” a phenomenon where cancer cells
exhibit accelerated glucose metabolism in the presence of oxygen. Hexokinase catalyzes the first committed
step in glucose metabolism by phosphorylating glucose to glucose-6-phosphate and thereby trapping glucose
in the cell to be used in various downstream pathways. Previous research has demonstrated that while normal
mammary gland cells do not express the hexokinase 2 (HK2) isoform, it is highly overexpressed in breast
cancer cells, which, in part, is responsible for the accelerated glucose utilization in primary tumors. HK2
deletion inhibits the tumorigenicity of cancer cells in vitro and in vivo. More importantly, systemic deletion of
HK2 after tumor onset inhibits tumor development without any adverse physiological consequences in mouse
models of cancer. Specifically, HK1 expression levels are sufficient for normal cellular function, but the cancer
cells cannot overcome the loss of HK2. As a result, HK2 appears to be a good potential target for therapeutic
treatment of primary breast cancer tumors. However, metastasis accounts for the high mortality rate in breast
cancer, which makes it more important to elucidate the role HK2 has in breast cancer metastasis. In fact,
preliminary results showing that systemic deletion of HK2 after tumor onset in a mouse model of breast cancer
metastasis profoundly inhibits metastasis. The proposed research plan will help elucidate the specific
mechanism(s) for HK2's role in breast cancer metastasis. The level of HK2 expression dramatically affects to
the level of epithelial mesenchymal transition (EMT) protein expression, specifically the important transcription
factor SNAIL. In addition, HK2 acts as scaffold to promote the phosphorylation and subsequent inactivation
Glycogen Synthase Kinase 3 (GSK3β). SNAIL is phosphorylated by GSK3β, which it turn leads to the
degradation of SNAIL. SNAIL is also regulated by O-GlcNAc modification, which helps to stabilize the protein
level by suppressing its GSK3β phosphorylation-mediated degradation. Aim 1 will investigate the mechanism
for HK2's role in EMT regulation. Furthermore, it is possible that breast cancer cells upregulate HK2 to combat
the increased energetic stress that occurs during metastasis. Research has shown that anti-oxidants can
enhance the metastatic potential in various cancers. The upregulation of HK2 can increase metabolite flux
through the pentose phosphate pathway for NADPH, thereby allowing cells to recycle anti-oxidants, such as
gluthathione. Aim 2 will determine HK2's role in intracellular levels of reactive oxygen species in relation to
breast cancer metastasis. Overall, this study utilizes a comprehens...

## Key facts

- **NIH application ID:** 9968167
- **Project number:** 5F30CA228191-03
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Catherine Blaha
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 5
- **Project period:** 2018-08-16 → 2022-08-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9968167

## Citation

> US National Institutes of Health, RePORTER application 9968167, Elucidating the Mechanisms by which Hexokinase 2 Regulates Breast Cancer Metastasis (5F30CA228191-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9968167. Licensed CC0.

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