Can Dietary Phytoestrogens Slow Down Prostate Tumor Proliferation? A Randomized Study (PRODICA)

Data from ecologic and experimental studies clearly show a protective effect of dietary phytoestrogens against prostate cancer. Genetic factors are also of etiologic importance in prostate cancer and there is growing evidence for the importance of a gene-diet interaction in prostate cancer progression. The investigators have recently found a putative genetic interaction for this protective role of phytoestrogens. The overall decreased risk of prostate cancer in men with a high intake of phytoestrogens was strongly modified by a nucleotide sequence variant in the estrogen receptor-beta (ERß) gene. An American study found a similar interactive effect between intake of phytoestrogens, as well as body mass index (BMI), and another nucleotide sequence variant in ERß.The phytoestrogens isoflavonoids and coumestans bind tightly to the estrogen receptor-beta (ERß) and are mainly found in soy and other beans. ERß expression has been found to be involved in progression of prostate cancer, suggesting that phytoestrogens may interact with ERß in the development of prostate cancer. With regard to potential carcinogenic mechanisms, phytoestrogens may be involved in the endocrine control of prostate cell growth by influencing the balance between AR and ERß.Testosterone and its metabolite 5α-dihydrotestosterone (DHT) cause proliferation of prostate epithelial cells through binding to the AR. In contrast, by binding to ERß, 5α androstane-3ß,17ß-diol (3ßAdiol), a metabolite of DHT, represses the expression of AR and thereby inhibits androgen-driven proliferation while promoting cell differentiation. In terms of proliferation, current data suggests a combined stimulatory role of ERα and AR in the prostate whereas ERß inhibits proliferation and stimulates differentiation. Both estrogen ERα and ß have affinity for estradiol whereas phytoestrogens and 3ßAdiol selectively activate ERß. Phytoestrogens should, as a result, be able to restrict cancer growth by acting as a substitute for 3ßAdiol. This is confirmed by experimental studies.

Results from previous intervention studies have given promising results indicating that certain dietary or lifestyle modifications can influence the progression of prostate cancer, although most of these studies have been of fairly short of duration and based on relatively small numbers of patients. For example, a randomised study showed that men who were given a dietary addition of flaxseeds had a lower percentage of positive cells containing the proliferation marker Ki-67 than men who had not received this addition to their diet. Taken together, the present evidence points towards the possibility for prostate cancer patients to complement with lifestyle-related treatment alternatives to prevent or delay tumor progression.

Specific aim: To perform a controlled randomized dietary intervention study in men with prostate cancer. The investigators will pursue the following specific aims/hypothesis:

1. "Among men with prostate cancer of intermediate risk-level, a diet high in phytoestrogens will reduce tumor progression compared to men with a diet low in phytoestrogens".
2. "The effects of a diet high in phytoestrogens on prostate cancer tumor progression differ between men with different genotypes of polymorphisms in the ERß gene". The men will be divided into two subgroups, those bearing TT or TC/CC alleles, of the single-nucleotide polymorphism (SNP) rs2987983-13950 T/C in the ERß-gene, in which the hypothesis will be tested.
3. To determine whether RNA expression of the AR, ERα and ERβ in prostate tumor tissue, as well as levels of steroid hormones, differs between men with a diet high and low in phytoestrogens, respectively, or between different genotypes of the ERβ gene.
4. To determine whether mRNA expression of genes involved in proliferation and ER signal pathways analyzed by whole transcriptomic profiling in prostatectomy specimens differs between men with a diet high and low in phytoestrogens, respectively, or between different genotypes of the ERβ gene.

Study protocol: Trough treating physicians, the investigators will identify 240 men in the Västra Götaland healthcare region who have been diagnosed with prostate cancer of intermediate risk-level (T1-T2, Gleason score <8, PSA<20)scheduled for radical prostatectomy. The clinic will be informed of which patients have been enrolled in the study, and the surgery for these patients will be scheduled six weeks ahead of time from the date of inclusion. Once a patient has agreed to participate, he will be randomized to one of the two intervention arms. The patient will then receive additional information depending on which group he belongs to and will be asked to donate a blood sample. Under normal clinical routine, data on all prostate cancer cases is collected in the National Prostate Cancer Register (NPCR), for example information on Gleason score, tumor volume, Prostate-specific antigen (PSA) levels. The investigators will collect information from the registry in connection with the analysis of data.