Researchers have uncovered three ways FOXA1 (Forkhead box A1) gene mutations override normal biology to drive an estimated one-third of prostate cancers. Dubbed FAST, FURIOUS and LOUD, the three mechanisms are described in a paper by researchers at the University of Michigan Rogel Cancer Center. Their findings were published in Nature, June 26.
Prostate cancer is thought to be mainly driven by androgens, so anti-androgen receptor treatment is a mainstay of therapy. But recurrence and advanced disease are still challenges and fueling the search for new therapeutics. Prostate cancer is the second most common cause of death in American men, and about one in nine men will develop the disease.
FOXA1 is a transcription factor essential for the normal development of several endoderm-derived organs, including the prostate gland. It has previously been reported to have both tumor-suppressiveand oncogenic roles, and is frequently mutated in hormone-receptor-driven prostate, breast, bladder and salivary-gland tumors. This latest study helps to clarify FOZA1’s role as a driver oncogene.
The Rogel researchers carried out RNA sequencing on 1,546 prostate cancer samples, including some from the Rogel Cancer Center’s Mi-ONCOSEQ program. They observed that FOXA1 alterations fall into three structural classes that diverge in clinical incidence and genetic co-alteration profiles. At least one of these three alterations was present in approximately 35% of the samples.
“We found that the same gene can be turned into an oncogene in three different ways,” says Abhijit Parolia, a molecular and cellular pathology graduate student and co-first author on this study. “One moves fast in the nucleus, the second binds to chromatin furiously and the third amplifies itself to be loud. These three alteration classes have different clinical implications for patients.”
The FAST, or class 1 mutations, let the transcription factor to travel more quickly along the DNA, allowing the partnering androgen receptor to activate expression of cancer-promoting genes. FAST mutations are most often seen in early stage prostate cancer and likely trigger the disease.
FURIOUS, or class 2 mutations, cut off a portion of the FOXA1 molecule. This truncated molecule binds tightly to the DNA, blocking normal FOXA1. FURIOUS mutations are found in hormone-therapy resistant prostate cancer and promote the cancer’s spread to distant sites.
Class 3 mutations are LOUD. They involve complex rearrangements of the FOXA1 genomic position, creating duplications in which FOXA1 or other oncogenes are overexpressed. This can occur in both early stage and metastatic cancer. FAST and FURIOUS mutations are mutually exclusive but LOUD rearrangements can occur by themselves or with either of the other two.
The study underlines FOXA1’s central role in mediating androgen receptor-driven oncogenesis. It also provides insights on how different types of FOXA1 alterations promote the initiation or spread of prostate cancer.
Senior study author Arul M. Chinnaiyan, M.D., Ph.D., says these new findings about FOXA1 could help identify patients with more aggressive disease or begin to understand why some men respond to therapy differently. Chinnaiyan is director of the Michigan Center for Translational Pathology and S.P. Hicks Endowed Professor of Pathology at Michigan Medicine.
“Oncogenes tend to be easier to develop therapies for as you could theoretically block them with targeted medicines,” Chinnaiyan explained in a press release. “However, FOXA1 is a challenging target because it is a transcription factor, a class of proteins notoriously difficult to inhibit with small molecules. However, scientists are now developing innovative strategies to go after these ‘undruggable’ targets.”
