If a prostate cancer cell were a car, the androgen receptor (AR) would be part of its ignition system, enabling cancer cells to respond to hormonal signals that drive growth.
For decades, therapies for advanced prostate cancer have focused on blocking this pathway, essentially trying to stop tumor growth by cutting off the hormonal fuel that AR signaling depends on.
But the most aggressive cancers often find ways around these treatments, restoring AR signaling through alternative mechanisms and making the disease much harder to control.
A better understanding of how prostate cancer maintains AR signaling, and what proteins help support it, could reveal new therapeutic vulnerabilities.
In a new study published in the journal Nature Genetics, Haolong Li, PhD, a researcher at Fred Hutch Cancer Center, and colleagues developed a way to monitor AR levels inside living tumor cells, and then used that tool to systematically identify genes that prostate cancer cells depend on to maintain AR levels.
Their work revealed an unexpected regulator: PTGES3, a relatively understudied protein that turns out to be essential for AR-driven prostate cancer survival, including in therapy-resistant disease.
The method also provides a new way to study other hormone-driven cancers, including breast cancer, which rely on similar signaling systems.
Li, who joined Fred Hutch’s Human Biology Division in 2024, began this work during his postdoctoral training at the University of California, San Francisco, working with mentors, the late Felix Feng, MD, and Luke Gilbert, PhD.
The team wanted to identify, without preconceptions, all the genes that help maintain AR in prostate cancer cells. Studying AR regulation, however, is challenging, because the most informative insights come from observing AR behavior directly in living cells.
To do this, the researchers built a live-cell AR reporter system.
They genetically engineered prostate cancer cells so that the AR protein would glow green when it was present, allowing the team to measure AR abundance in real time without disrupting its normal function.
Instead of attaching a bulky fluorescent tag that could interfere with AR biology, they used a split-tag strategy: a small piece was incorporated into the AR gene itself, while the complementary piece was supplied separately. Only when the two halves came together did the AR protein light up.
“We spent a year getting this to work,” Li said. “It was a lot of trial and error.”
This approach gave the team a powerful way to track changes in AR levels dynamically in living tumor cells.
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With this glowing AR system in hand, the researchers performed a genome-scale CRISPR-based screen.
By systematically turning down thousands of genes one at a time, they asked a simple question: which genes are required for prostate cancer cells to maintain AR protein levels?
Cells that lost their green signal pointed to genes that help keep AR stable and abundant.
The screen recovered known AR regulators, validating the approach. But it also revealed something unexpected: PTGES3 emerged as one of the strongest hits.
PTGES3 had not been well studied in prostate cancer. It has been linked to inflammation and steroid receptor chaperoning, but its role in AR-driven disease was unclear.
When the team suppressed PTGES3, AR protein levels dropped sharply. Prostate cancer cells stopped dividing, entered cell-cycle arrest and ultimately died.
Importantly, this effect was observed not only in standard AR-driven prostate cancer models, but also in aggressive and drug-resistant settings, including cancers resistant to enzalutamide, a drug used to treat certain types of prostate cancer.
Clinical tumor data further showed that PTGES3 expression is associated with resistance to AR-directed therapies, suggesting it may play a role in the most difficult-to-treat forms of prostate cancer.
PTGES3 was previously thought to act mainly outside the nucleus, helping stabilize steroid receptors in the cytoplasm.
But the researchers discovered that PTGES3 does more than that.
PTGES3 also appears inside the nucleus, where AR binds DNA and activates gene programs that drive tumor growth. Rather than acting only as a supporting chaperone outside the nucleus, PTGES3 plays a direct role in AR’s function at its target genes.
When reviewers asked how PTGES3 might influence AR activity in the nucleus, Li connected with University of Texas Health at San Antonio structural biologist Elizabeth Wasmuth, PhD, whose expertise helped strengthen the mechanistic story. Jasmine Anderson, a trainee in Li’s lab, assisted with revisions to the study and its interpretation.
Using a combination of biochemical experiments and structural modeling, the team showed that PTGES3 binds directly to AR and helps AR engage chromatin, an essential step in activating AR-regulated genes.
In other words, PTGES3 is not only helping maintain AR stability, it is also supporting AR’s function inside the nucleus.
The discovery of PTGES3’s essential role highlights a potential vulnerability in advanced prostate cancer.
Many therapy-resistant tumors escape treatment by restoring AR signaling through amplification, mutation, splice variants, or other mechanisms. Because these resistance pathways ultimately converge on maintaining AR activity, targeting a key AR-support factor like PTGES3 could represent a new therapeutic strategy.
By identifying PTGES3 as an essential AR partner, the study points to a new way to attack prostate cancers that have become resistant to current AR-targeted therapies.
The findings may also have broader implications beyond prostate cancer. Other hormone-driven cancers, including breast cancer, rely on related nuclear receptor pathways.
Now at Fred Hutch, Li’s lab is building on these findings through collaborations with colleagues including prostate cancer biologist Peter Nelson, MD, with the long-term goal of translating this biology into new therapeutic opportunities for patients with advanced disease. Nelson holds the Stuart and Molly Sloan Precision Oncology Institute Endowed Chair.
The study was supported by the Prostate Cancer Foundation, the Pacific Northwest Prostate Cancer SPORE, the Institute for Prostate Cancer Research, the Mike Slive Foundation for Prostate Cancer Research, grants from the National Institutes of Health, and multiple collaborative research programs focused on improving outcomes for patients with advanced, drug-resistant prostate cancer.
John Higgins, a staff writer at Fred Hutch Cancer Center, was an education reporter at The Seattle Times and the Akron Beacon Journal. He was a Knight Science Journalism Fellow at MIT, where he studied the emerging science of teaching. Reach him at jhiggin2@fredhutch.org or @jhigginswriter.bsky.social.
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