Related Experiment Video

Updated: Sep 15, 2025

Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
10:36

Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer

Published on: March 17, 2016

10.6K

Metabolomic Profiling Reveals Key Metabolic Alterations in MCF7 Tamoxifen-Resistant Cells Following EPAS1 Inhibition

Enzhi Luo1, Neeraj Manvi Agarwal1, Junjeong Choi1

  • 1Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy, Yonsei University, Incheon 21983, South Korea.

Journal of Proteome Research
|July 17, 2025
PubMed

Insights

Tamoxifen resistance in breast cancer is linked to EPAS1-driven metabolic changes. Inhibiting EPAS1 with PT2977 may restore tamoxifen sensitivity by normalizing cell metabolism.

Area of Science:

  • Molecular Biology
  • Cancer Metabolism
  • Drug Resistance

Background:

  • Tamoxifen (TAM) is a primary treatment for luminal A breast cancer.
  • Acquired resistance to TAM presents a major clinical obstacle.
  • Understanding resistance mechanisms is crucial for improving patient outcomes.

Purpose of the Study:

  • To investigate the role of EPAS1 (HIF-2α) in tamoxifen resistance.
  • To explore EPAS1-driven metabolic reprogramming under hypoxia.
  • To evaluate the efficacy of EPAS1 inhibitor PT2977 in overcoming TAM resistance.

Main Methods:

  • Comparative transcriptomic analysis of resistant vs. sensitive cells.
  • Untargeted LC-MS/MS metabolomics to identify altered metabolites.
  • Investigating the impact of EPAS1 inhibition on metabolic pathways and cell viability.

Main Results:

  • Resistant cells showed upregulated EPAS1 and enriched hypoxia-associated pathways (JAK-STAT, TGF-beta, lipid metabolism).
  • Significant dysregulation in glutamate, glutathione, Warburg effect, and fatty acid oxidation was observed.
  • EPAS1 promoted fatty acid uptake (CD36) and glutamine metabolism (SLC1A5), aiding survival.
  • PT2977 treatment normalized metabolite profiles and reduced cell viability.

Conclusions:

  • EPAS1-mediated metabolic reprogramming is a key driver of tamoxifen resistance.
  • EPAS1 inhibition by PT2977 shows promise for overcoming resistance in luminal A breast cancer.
  • Targeting EPAS1 offers a potential therapeutic strategy for resistant breast cancer.
Keywords:
EPAS1PT2977hypoxiametabolomics.tamoxifen resistance

More Related Videos

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells06:54

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells

Published on: October 27, 2020

13.3K
Using Microarrays to Interrogate Microenvironmental Impact on Cellular Phenotypes in Cancer08:20

Using Microarrays to Interrogate Microenvironmental Impact on Cellular Phenotypes in Cancer

Published on: May 21, 2019

5.7K

Related Concept Videos

Electron Transport Chain: Complex I and II01:46

Electron Transport Chain: Complex I and II

The mitochondrial electron transport chain (ETC) is the main energy generation system in the eukaryotic cells. However, mitochondria also produce cytotoxic reactive oxygen species (ROS) due to the large electron flow during oxidative phosphorylation. While Complex I is one of the primary sources of superoxide radicals, ROS production by Complex II is uncommon and may only be observed in cancer cells with mutated complexes.
ROS generation is regulated and maintained at moderate levels necessary...
15.0K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
3.9K
Mitogens and the Cell Cycle02:38

Mitogens and the Cell Cycle

Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
6.9K