The FOXA1 Gene in Prostate Cancer: Fast, Furious, and Loud

Gene forkhead box A1 (FOXA1) overrides normal biology in 3 different ways to drive prostate cancer, aptly named FAST, FURIOUS, and LOUD for their functions, according to a new study led by researchers from the University of Michigan Rogel Cancer Center

FOXA1 has been previously known to be mutated in prostate cancer; however, its biological functions were not understood well. Moreover, the researchers were uncertain if FOXA1 was an oncogene that accelerated cancer or suppressed it.

Gene FOXA1 is essential for the normal development of several endoderm-derived organs, including the prostate gland, but is frequently mutated in hormone-receptor-driven prostate, breast, bladder, and salivary gland tumors, according to the study.

Published in Nature, the study found the increased prevalence of FOXA1 by using RNA sequencing data from approximately 1546 prostate cancer samples from multiple collections, including the Rogel Cancer Center’s Mi-ONCOSEQ program.

The following mutations were found within the DNA samples:

• Class 1 mutations are FAST, known to cause the transcription factor to travel more quickly through the DNA, allowing the partnering androgen receptor to activate expression of cancer-promoting genes. These are seen in early stage prostate cancer and are likely what triggers the disease.
• Class 2 mutations are FURIOUS, known to cause a portion of the FOXA1 molecule to be cut off. This truncated molecule binds very strongly to the DNA, preventing normal FOXA1 from binding. These mutations are often found in lethal hormone-therapy resistant prostate cancer and promote the cancer’s spread to different sites.
• Class 3 mutations are LOUD, and involve complex arrangements of the FOXA1 genomic position, creating duplications involving overexpression.

The authors noted that oncogenes are easier to develop therapies for, as they could be blocked by targeted medicines; however, FOXA1 is a transcription factor, which makes it a difficult target. They concluded that this information can be used to identify patients with more aggressive disease or help understand why patients respond to therapy differently.

Reference

• Chinnaiyan AM, Parolia A, Cieslik M, et al. Distinct structural classes of activating FOXA1 alterations in advanced prostate cancer. Nature. 2019. https://www.nature.com/articles/s41586-019-1347-4
• Newly Defined Cancer Driver is Fast, Furious and Loud [news release]. University of Michigan Health Lab website. Published June 26, 2019. https://labblog.uofmhealth.org/lab-report/newly-defined-cancer-driver-fast-furious-and-loud. Accessed June 28, 2019.