Distinct FOXA1 Mutations Drive Prostate Cancer Initiation and Therapy Resistance

A recent study from the University of Michigan Rogel Health Cancer Center, published in Science, has provided significant insights into the role of FOXA1 gene mutations in prostate cancer development and treatment resistance. Researchers identified two primary mutation classes in FOXA1, a key transcription factor involved in androgen receptor DNA binding, which is frequently altered in 10–40% of hormone-dependent prostate cancers.

Using innovative mouse models, scientists uncovered how each mutation class contributes to different stages of disease progression. The first class, predominantly found in primary prostate cancers, works synergistically with loss of the tumor suppressor gene TP53, promoting the formation of aggressive yet hormone-sensitive tumors that respond to androgen deprivation therapy. The second class, often associated with metastatic prostate cancer, does not directly initiate tumor growth but alters cellular lineage identity, enabling tumors to evade hormonal therapies and develop therapy resistance.

This research marks the first in vivo demonstration of FOXA1's causal role in prostate cancer initiation. Prior studies relied mostly on cell lines, but these animal models provide clear evidence of FOXA1 mutations driving tumor development and progression.

Furthermore, the findings elaborate on how mutations within the same gene can have opposite functional impacts—initiating tumor formation in early stages or fostering therapy resistance in advanced disease. Understanding these mechanisms offers promising avenues for developing mutation-specific therapies and improving treatment strategies.

In hormone-sensitive prostate cancer, tumor growth relies on continuous androgen signaling, but resistance often develops, complicating treatment. The mouse models demonstrated that tumors with Class 1 mutations depend on androgen presence, serving as a valuable tool for preclinical testing. Conversely, Class 2 mutations reprogram gene activation at latent DNA sites, allowing tumors to adapt and survive despite androgen blockade, thus escaping therapy.

This discovery deepens our understanding of prostate cancer evolution and highlights the importance of FOXA1 mutations as potential targets for tailored treatments, ultimately aiming to improve patient outcomes.