Characterization of Novel Liver X Receptor Inverse Agonist in Breast Cancers

Breast cancer is the second most diagnosed cancer type in women and is responsible for approximately 13% of cancer-related mortalities. Significant advances have been made in breast cancer therapy to date. However, the development of targeted therapies remains essential to overcome the lack of treatment options for TNBCs and acquired resistance. Metabolic reprogramming, wherein cancer cells rewire their metabolism for growth and survival, is a critical area of interest. Developing anti-metabolic drugs is an emerging field that targets the upregulated metabolic dependence of cancer. The liver X receptors (LXR) are ligand-modulated nuclear receptors. LXR activation upregulates the expression of genes involved in altered metabolic pathways in cancer, including cholesterol transport, glucose, and lipid metabolism. Moreover, LXR inhibition using the inverse agonist SR9243 has been shown to disrupt glycolysis, de novo lipogenesis, and induce antitumor immunity. In our lab, we discovered another cancer-specific LXR inverse agonist, GAC0001E5 (1E5), in pancreatic ductal adenocarcinoma (PDAC). Treatment with 1E5 has been demonstrated to inhibit glutaminolysis and induce oxidative stress. Additionally, LXRβ transcript levels are upregulated in breast cancer patient tissue. Therefore, we posit that characterization of the effects of 1E5 in breast cancer can reveal potential antitumor effects. Compared to LXR agonist GW3965, inverse agonist 1E5 treatment markedly disrupted breast cancer cell proliferation by downregulating LXR target genes and inducing LXRβ protein degradation. Mechanistic evaluations of 1E5 revealed that it downregulates glutamine metabolism in breast cancers. Specifically, 1E5 downregulated glutaminase 1 (GLS1) gene expression, leading to decreased levels of intracellular glutamate and glutathione, which elevated oxidative stress due to the accumulation of reactive oxygen species (ROS). Moreover, targeting FASN, a de novo lipogenesis enzyme, is an emerging target in HER2-positive breast cancer. Treatments with 1E5 reduced FASN and HER2 protein levels. Here, we suggest that there is a potential crosstalk between LXR, FASN, and HER2, and that inhibition by 1E5 can downregulate HER2-mediated oncogenic signaling and induce apoptosis. Taken together, these findings lay the foundation for the use of pharmacological LXR inhibition as a potential therapeutic strategy in targeting various aspects of breast cancers.

Name thesis:degree_name

Doctor of Philosophy

Discipline thesis:degree_discipline

Biochemistry

Grantor

University of Houston

Year dc:date.issued

2024

Author dc:creator

• Premaratne, Asitha N

Advisor dc:contributor.advisor

• Lin, Chin-Yo

Committee members dc:contributor.committeemember

• Feng, Qin
• Filgueira, Carly S
• Bawa-khalfe, Tasneem

• Molecular biology
• Biochemistry

Language dc:language.iso

en

Handle dc:identifier.uri

https://hdl.handle.net/10657/19918

OAI identifier oai:identifier

oai:uh-ir.tdl.org:10657/19918