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The FOXA1 gene is an important driver of prostate cancer formation and growth

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When back-to-back articles are published in one of the world’s top scientific journals, Nature, we know that something exciting is going on. Scientists from two different laboratories have discovered the mechanisms by which a gene called FOXA1 drives prostate cancer formation. FOXA1 is therefore a potential target for new drugs to block growth of prostate cancer.   

Changes to DNA are the main cause of cancer

Changes to DNA are the underlying cause of cancers. Risk factors such as age or exposure to radiation ultimately lead to changes in DNA. These DNA changes cause normal cells to change into tumour cells. DNA problems are commonly found in tumour cells. A lot of research has gone into working out what these changes are. This has been very useful for developing new therapies and understand how cancer is formed.

The sequence of human DNA carries instructions to make proteins. These instructions are called genes. Genes make up less than 10% of our DNA. The rest of the DNA has many other roles. One of these roles is to control when and where genes are switched on to make proteins. There are patches of DNA surrounding genes that can be used to control when the gene is switched on, therefore controlling production of specific proteins. Molecules called transcription factors bind to these small DNA patches, to control the use of genes.

The FOXA1 gene

FOXA1 is a transcription factor; it controls when and where other genes are used. FOXA1 protein is made from the DNA of the FOXA1 gene. If there are mutations in this gene, it affects the function of the FOXA1 protein.

FOXA1 is known as a pioneer gene. It’s thought to play an important role in the change from normal cells to tumour cells. There are also numerous DNA mutations found in the FOXA1 gene in some prostate tumours. Metastatic prostate tumours (that have spread away from the prostate gland) often contain too much FOXA1. Men with a high amount of FOXA1 in their tumours are more likely to have worse outcomes from the cancer. We know that FOXA1 regulates the production of androgen receptor proteins. These receptors detect the presence of hormones like testosterone. Androgen receptors are required by prostate cancer cells for growth.

There is an important link between FOXA1 and the androgen receptor. FOXA1 activity is proposed to increase the ability of the androgen receptor to switch on cancer-promoting genes in the tumour cells.

There are many mutations that have been found in FOXA1 in prostate cancer cells. But we don’t know exactly how these FOXA1 mutations are affecting these cells and contributing to the formation of prostate cancer.

Two important articles about FOXA1 mutations in prostate cancer

Michigan study

The first article was published by a group of researchers from the University of Michigan, USA. The senior author is Prof Arul Chinnaiyan, director of the Michigan Center for Translational Pathology and Professor of Pathology at Michigan Medicine.

The Michigan research group acquired 1,546 prostate tumour samples for their study. Of these, 888 were localised to the prostate gland and 658 were metastatic, which had spread elsewhere. 35% of these tumours had one or more mutation in the FOXA1 gene. The researchers characterised all the mutations they found. These included point mutations (where a single DNA unit is changed), larger regions that were changed, and structural rearrangements (where large pieces of the gene were missing or duplicated).

The results from this study found three different classes of FOXA1 mutation that promoted tumour growth in different ways. The University of Michigan press release usefully describes these classes as fast, furious and loud.

Class 1 mutations are described as FAST. These FOXA1 mutations cause the transcription factor to travel more quickly through the DNA. This increases the rate by which the androgen receptor activates expression of cancer-promoting genes. These mutations are seen in early stage prostate cancer and are likely what triggers the disease. Most of the mutations in FOXA1 are in class 1.

Class 2 mutations are FURIOUS. These changes to DNA causes a portion of the FOXA1 molecule to be cut off. This shortened molecule binds very strongly to the DNA, preventing normal FOXA1 from binding. These mutations are found in late stage, aggressive prostate cancers. They promote spreading to distant sites by metastasis.

Class 3 mutations are LOUD. They involve structural rearrangements of the FOXA1 gene. An example is called gene duplications, where multiple copies of the gene are made. This increases the amount of FOXA1 protein produced. More FOXA1 protein means a stronger influence on androgen receptors, driving prostate cell growth.

New York study

The second report from New York examined the FOXA1 gene to look for where mutations are usually found. The senior author on this study is Prof Charles Sawyers from the Memorial Sloan Kettering Cancer Center.

The New York team assembled a group of 3,086 prostate tumour samples. By studying all the mutations in the FOXA1 gene, they defined two hotspots where mutations are commonly found. One is called the Wing2 region. About half of all FOXA1 mutations are found in this area. Wing2 region mutations were found in tumours know as adenocarcinomas. This is the most common type of prostate cancer. These mutations were found at all stages – localised and advanced. Wing2 mutations were shown to have cancer-pioneering activity. The researchers proposed that changes to the gene in this region are contributing to the change from normal cells into cancer cells.

The second mutation hotspot is a region called R219. About 5% of all mutations were found in this area. Cancers that had R219 mutations were more likely to have features of neuroendocrine prostate tumours – a rarer, aggressive form of prostate cancer.

 

These two important studies help scientists to understand what has gone wrong in normal cells that drives their change into cancer cells. The FOXA1 gene is a potential target for new drugs to block prostate cancer growth.   

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