Inactivation of the PRH/HHEX tumour suppressor and its effects on inflammatory signalling in prostate cancer.

Prostate cancer is the most common cancer in men in the UK and this disease has a particularly high incidence in men of African origin. Around 50,000 new cases are diagnosed each year and this is increasing as men live longer. Most men diagnosed with prostate cancer do not die from this disease.

However, for patients with disease that has spread to other sites in the body, surgical castration is the recommended treatment. For patients with less advanced disease radiotherapy and/or drug treatments are effective. However, these treatments can have serious side effects including osteoporosis and bone fracture.

In many less advanced cases treatment is probably unnecessary as the cancer is very unlikely to progress and spread. Better ways of identifying patients who need treatment and better treatments would be of immense value to patients and result in major cost savings for the NHS. The incidence of prostate cancer in Kenya and other low- and middle-income countries (LMIC) is also rising and in these countries the cost of treatment and the cost of lives lost to this disease are major barriers to economic development.

The aims of this project are to improve our understanding of the causes of prostate cancer progression and to create an archive of prostate cancer samples that will be of value to this study and to future work in this area.

Inflammation in the prostate is common and this is known to be an important factor in prostate cancer. Inflammation in the prostate in LMIC and UK patients can have many causes including bacterial and viral infections and autoimmune responses. Cells from the immune system are found in the prostate and in prostate cancers they release signals that increase the replication of cancer cells and increase their ability to spread.

We have discovered that a protein called PRH stops prostate cells from replicating and stops them from invading other tissues. We found that as prostate cancer becomes more advanced the activity of PRH is decreased in three ways: first, the PRH protein is inactivated by a modification known as phosphorylation; second, the gene that normally produces PRH is stopped from making PRH; and third, this gene is deleted altogether in some cancer cells.

Our work showed that the PRH protein works by controlling the activity of many genes important in allowing prostate cells to respond to signals from immune cells and in particular we showed that PRH controls the response to a molecule called Transforming Growth Factor beta (TGFb) released from some types of immune cell. In addition we have shown that TGFb itself controls PRH activity by decreasing how much PRH is produced by the PRH gene and by increasing phosphorylation of PRH.

We will investigate the importance of immune cells and immune signals in prostate cancer in Kenya and in the UK and find out how changes in the levels and activity of PRH alter the response of prostate cells to TGFb and other immune signals. To achieve this we will collect blood, urine, and cancer samples from Kenyan patients and document the clinical history associated with prostate cancer in these patients using questionnaires.

We will then determine the levels of PRH and phosphorylated PRH in Kenyan and UK prostate cancer samples using a technique called immunohistochemistry (IHC) that allows us to visualise proteins in cancer cells. We will also measure the levels of inflammatory signals and immune cells in the Kenyan blood samples. Finally we will determine how changes in PRH levels and activity influence how prostate cells respond to signals from immune cells and how these signals control PRH levels.

These studies will advance our understanding of how immune signals are involved in prostate cancer. They will also tell us whether measuring the levels of immune signals in blood and PRH or phosphorylated PRH in prostate cancer might be a good ways to predict which patients require treatment.