A new study from researchers at the University of Michigan Rogel Cancer Center finds; that the gene FOXA1 overrides normal biology in three different ways to drive prostate cancer. They refer to the three classes as fast, furious, and loud to reflect their unique features. The findings are publish in Nature. The Fast and the Furious movie franchise meets the Fast N’ Loud television series to define an oncogene that drives 35% of prostate cancers.
However, we found that the same gene can be turn into an oncogene in three different ways. One moves fast in the nucleus, the second binds to chromatin furiously and the third amplifies itself to be loud. But these three alteration classes have different clinical implications for patients.” Abhijit Parolia; a molecular and cellular pathology graduate student and co-first author on this study.
Fast and furious mutations
Class 1 mutations are FAST. They cause the transcription factor to travel more quickly through the DNA; allowing the partnering androgen receptor to activate expression of cancer-promoting genes. Imagine the driver racing forward at high speed. And these mutations is seen in early stage prostate cancer and is likely what triggers the disease.
However, class 2 mutations are FURIOUS. The mutation causes a portion of the FOXA1 molecule to cut. This truncate molecule binds very strongly to the DNA, preventing normal FOXA1 from binding. This mutations is found in lethal hormone-therapy resistant prostate cancer; and promote the cancer’s spread to distant sites. Think of the mutant as furiously binding DNA and dominantly enabling the cancer’s aggressive features.
But Class 3 mutations are LOUD. They involve complex rearrangements of the FOXA1 genomic position; creating duplications in which FOXA1 or other oncogenes are overexpress. In other words, the amplify oncogenes work at top volume to be biologically heard. This can occur in both early stage and metastatic cancer. However, fast and furious mutations are mutually exclusive but loud rearrangements; can exist by themselves or mingle with either of the other two.
FOXA1 known to be mutate in prostate cancer
FOXA1 is previously known to be mutate in prostate cancer, but its biological functions are poorly understood. Scientists were uncertain if FOXA1; was an oncogene that fuel cancer and tumor suppressor that hit the brakes. The Rogel Cancer Center team now clarify FOXA1’s role as a driver oncogene; in addition to classifying the three novel FOXA1 alterations.
However, the researchers discover its increase prevalence by using RNA sequencing data from 1,546 prostate cancer samples; from multiple collections, including the Rogel Cancer Center’s Mi-ONCOSEQ program. “Oncogenes tend to be easier to develop therapies for as you could theoretically block them with targeted medicines,” Chinnaiyan says. “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.”
But Chinnaiyan says this information can also be use to identify patients with more aggressive disease; or begin to understand why patients respond to therapy differently. However, the authors also show that the three classes of FOXA1 alterations is find in breast cancer; presumably impacting the estrogen receptor in a way similar to how it impacts the androgen receptor. FOXA1 alterations are implicate in bladder cancer.