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Sandy Srinivas, MD


FOXA1: Potential Therapeutic Target in Castration-Resistant Prostate Cancer?

By: Kayci Reyer
Posted: Tuesday, December 13, 2022

According to research presented in Oncogene, the protein FOXA1 may be a key factor in hypoxia programming in castration-resistant prostate cancer. FOXA1, an epithelial transcription factor, is critical in controlling the presence of oxygen in the tumor microenvironment, and its loss spurs hypoxia-fueled tumor progression.

“Our study reveals an essential role of FOXA1 in controlling the hypoxic tumor microenvironment and establishes the HIF1A-CCL2 axis as one mechanism of FOXA1 loss-induced castration-resistant prostate cancer progression,” noted Jindan Yu, MD, PhD, of Northwestern University Feinberg School of Medicine, Chicago, and colleagues.

Through in vitro cancer cell analysis, the study found that transcriptional hypoxia activity was triggered by the downregulation of FOXA1. This occurred when FOXA1 binds to another protein, HIF1A, and becomes downregulated. HIF1A then contributes to the regulation of the resulting hypoxia gene expression. The downregulation of FOXA1 also created an environment that the authors consider friendly to infiltration by macrophages. The study also found that the chemokine ligand CCL2 was targeted by the bound FOXA1-HIF1A axis. Targeted HIF1A-CCL2 therapies may reverse the uptick in macrophage infiltration and cancer cell invasion associated with FOXA1 downregulation, the investigators proposed.

“We [respectfully] disagree with people in the field suggesting to therapeutically target FOXA1, because it may lead to lineage plasticity, hypoxia and [castration-resistant prostate cancer] progression,” stated Dr. Yu. “We think you should really target epithelial-mesenchymal transition and hypoxia programs that are caused by FOXA1 loss to prevent or treat [castration-resistant prostate cancer].”

Disclosure: For full disclosures of the study authors, visit

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