Nav: Home

Newly defined cancer driver is fast, furious and loud

June 26, 2019

ANN ARBOR, Michigan -- The Fast and the Furious movie franchise meets the Fast N' Loud television series to define an oncogene that drives 35% of prostate cancers.

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 published in Nature.

"It's quite intriguing and complex biology," says senior study author Arul M. Chinnaiyan, M.D., Ph.D., director of the Michigan Center for Translational Pathology and S.P. Hicks Endowed Professor of Pathology at Michigan Medicine.

"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."

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. These mutations are seen in early stage prostate cancer and are likely what triggers the disease.

Class 2 mutations are FURIOUS. The mutation causes 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 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.

Class 3 mutations are LOUD. They involve complex rearrangements of the FOXA1 genomic position, creating duplications in which FOXA1 or other oncogenes are overexpressed. In other words, the amplified oncogenes work at top volume to be biologically heard. This can occur in both early stage and metastatic cancer.

Fast and furious mutations are mutually exclusive but loud rearrangements can exist by themselves or mingle with either of the other two.

FOXA1 was previously known to be mutated in prostate cancer, but its biological functions were poorly understood. Scientists were uncertain if FOXA1 was an oncogene that fueled cancer or a tumor suppressor that hit the brakes. The Rogel Cancer Center team now clarified FOXA1's role as a driver oncogene, in addition to classifying the three novel FOXA1 alterations.

The researchers discovered its increased 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."

Chinnaiyan says this information can also be used to identify patients with more aggressive disease or begin to understand why patients respond to therapy differently.

The authors also showed that the three classes of FOXA1 alterations are found in breast cancer, presumably impacting the estrogen receptor in a way similar to how it impacts the androgen receptor. FOXA1 alterations are implicated in bladder cancer and some salivary gland cancers as well.
-end-
Additional authors: Abhijit Parolia, Marcin Cieslik, Shih-Chun Chu, Lanbo Xiao, Takahiro Ouchi, Yuping Zhang, Xiaoju Wang, Pankaj Vats, Xuhong Cao, Sethuramasundaram Pitchiaya, Fengyun Su, Rui Wang, Felix Y. Feng, Yi-Mi Wu, Robert J. Lonigro, Dan R. Robinson

Funding: Prostate Cancer Foundation; National Cancer Institute grants U01 CA214170 and P50 CA186786; Stand Up 2 Cancer-PCF Dream Team grant SU2C-AACR-DT0712; Howard Hughes Medical Institute; A. Alfred Taubman Institute; American Cancer Society; Department of Defense grants W81XWH-17-1-0130, W81XWH-17-1-0224, W81XWH-16-1-0195

Disclosure: None

Reference: Nature, doi: 10.1038/s41586-019-1347-4, published online June 26, 2019

Resources:

University of Michigan Rogel Cancer Center, http://www.rogelcancercenter.org

Michigan Health Lab, http://www.MichiganHealthLab.org

Michigan Medicine Cancer AnswerLine, 800-865-1125

Michigan Medicine - University of Michigan

Related Prostate Cancer Articles:

The Lancet: Prostate cancer study finds molecular imaging could transform management of patients with aggressive cancer
Results from a randomised controlled trial involving 300 prostate cancer patients find that a molecular imaging technique is more accurate than conventional medical imaging and recommends the scans be introduced into routine clinical practice.
Common genetic defect in prostate cancer inspires path to new anti-cancer drugs
Researchers found that, in prostate cancer, a mutation leading to the loss of one allele of a tumor suppressor gene known as PPP2R2A is enough to worsen a tumor caused by other mutations.
First prostate cancer therapy to target genes delays cancer progression
For the first time, prostate cancer has been treated based on the genetic makeup of the cancer, resulting in delayed disease progression, delayed time to pain progression, and potentially extending lives in patients with advanced, metastatic prostate cancer, reports a large phase 3 trial.
Men taking medications for enlarged prostate face delays in prostate cancer diagnosis
University of California San Diego School of Medicine researchers report that men treated with medications for benign prostatic hyperplasia (enlarged prostate) experienced a two-year delay in diagnosis of their prostate cancer and were twice as likely to have advanced disease upon diagnosis.
CNIO researchers confirm links between aggressive prostate cancer and hereditary breast cancer
The study has potential implications for families with members suffering from these types of tumours who are at an increased risk of developing cancer.
Distinguishing fatal prostate cancer from 'manageable' cancer now possible
Scientists at the University of York have found a way of distinguishing between fatal prostate cancer and manageable cancer, which could reduce unnecessary surgeries and radiotherapy.
Researchers find prostate cancer drug byproduct can fuel cancer cells
A genetic anomaly in certain men with prostate cancer may impact their response to common drugs used to treat the disease, according to new research at Cleveland Clinic.
ASCO and Cancer Care Ontario update guideline on radiation therapy for prostate cancer
The American Society of Clinical Oncology (ASCO) and Cancer Care Ontario today issued a joint clinical practice guideline update on brachytherapy (internal radiation) for patients with prostate cancer.
Patient prostate tissue used to create unique model of prostate cancer biology
For the first time, researchers have been able to grow, in a lab, both normal and primary cancerous prostate cells from a patient, and then implant a million of the cancer cells into a mouse to track how the tumor progresses.
Moffitt Cancer Center awarded $3.2 million grant to study bone metastasis in prostate cancer
Moffitt researchers David Basanta, Ph.D., and Conor Lynch, Ph.D., have been awarded a U01 grant to investigate prostate cancer metastasis.
More Prostate Cancer News and Prostate Cancer Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: Reinvention
Change is hard, but it's also an opportunity to discover and reimagine what you thought you knew. From our economy, to music, to even ourselves–this hour TED speakers explore the power of reinvention. Guests include OK Go lead singer Damian Kulash Jr., former college gymnastics coach Valorie Kondos Field, Stockton Mayor Michael Tubbs, and entrepreneur Nick Hanauer.
Now Playing: Science for the People

#562 Superbug to Bedside
By now we're all good and scared about antibiotic resistance, one of the many things coming to get us all. But there's good news, sort of. News antibiotics are coming out! How do they get tested? What does that kind of a trial look like and how does it happen? Host Bethany Brookeshire talks with Matt McCarthy, author of "Superbugs: The Race to Stop an Epidemic", about the ins and outs of testing a new antibiotic in the hospital.
Now Playing: Radiolab

Dispatch 6: Strange Times
Covid has disrupted the most basic routines of our days and nights. But in the middle of a conversation about how to fight the virus, we find a place impervious to the stalled plans and frenetic demands of the outside world. It's a very different kind of front line, where urgent work means moving slow, and time is marked out in tiny pre-planned steps. Then, on a walk through the woods, we consider how the tempo of our lives affects our minds and discover how the beats of biology shape our bodies. This episode was produced with help from Molly Webster and Tracie Hunte. Support Radiolab today at Radiolab.org/donate.