Item Details

abstract

Epidemiologic studies have revealed marked disparities in prostate cancer incidence throughout the world. Prostate cancer incidence is estimated to be 10 to 60 times lower in Asian men living in their country of origin when compared to African American and Caucasian American men. The precursor lesion of prostate cancer, prostatic intraepithelial neoplasia, follows a similar epidemiologic pattern, being detected earlier and with greater frequency in American men than in Asian men. Disparate socioeconomic status, diagnostic screening, body mass index, serum and tissue hormone concentrations, prostate tissue sex steroid receptor expression levels, androgen and estrogen receptor polymorphisms, and diet have all been proposed to explain these discrepancies in prostate cancer incidence in men living in Western countries when compared to men living in Asia. Lifestyle factors became a more intense research focus when epidemiologic studies revealed that prostate cancer incidence doubles in Asian American immigrants living in the United States. However, the prostate cancer incidence in Asian immigrants still remains approximately half that of Caucasian American men, suggesting that epigenetic, genetic, and lifestyle differences likely ix play a role in prostate cancer development. One of the most salient lifestyle differences between American men and Asian men is their diet. Traditional Asian diets are rich in soy protein and lower in saturated fat than American diets. It is important to note that prostate cancer incidence is increasing worldwide, even in traditionally “low risk” countries. This increase in prostate cancer incidence is associated with the “nutrition transition” or consumption of “Westernized” diets that are more energy-dense, higher in animal protein, saturated fat, vegetable oil, simple sugars, and lower in fiber and phytochemicals. These diets are replacing more traditional diets rich in legumes, fiber, and cereals world-wide. Soy, a legume, contains polyphenolic, estrogen-like compounds termed isoflavonoids. Following the consumption of a soy-containing meal, isoflavonoids are absorbed in the gut, and can be detected in the serum in nanomolar concentrations. These polyphenolic compounds are structurally similar to the endogenous sex steroid hormone estradiol (17β estradiol) and are able to bind to endogenous estrogen receptors (ER) with varying affinities. There are two ER receptor subtypes, ERα and ERβ. Both ER subtypes are expressed in the prostate gland. Estrogen receptor α is preferentially expressed in the stroma and ERβ is preferentially expressed in the epithelium. The effects of estrogen and estrogen-like compounds are mediated through these two receptors, although in the prostate gland they are thought to have opposing effects. Estrogen receptor β expression is thought to have antiproliferative and anti-inflammatory effects, while ERα expression is thought to promote cell proliferation, squamous metaplasia, and inflammation or prostatitis. x We conducted two parallel studies to investigate the effects of soy isoflavonoid consumption on the prostate gland. The purpose of our first study was to investigate the effects of isoflavonoids in the normal prostate gland. We used the cynomolgus macaque (Macaca fascicularis) model, a species sharing 97% genetic homology with humans for this placebo-controlled dietary study. We found no significant adverse effects of isoflavonoid consumption on the prostate gland in these 91 adult male macaques receiving: 1) a soy-free, casein-lactalbumin-based diet (n=30), 2) a low-soy isoflavonoid diet, approximating 75 mg human equivalents per day (n=30), or 3) a high-soy isoflavonoid diet, approximating 150 mg human equivalents per day (n=31) for 31 months. The purpose of our second study was to investigate the epigenetic effects of short-term isoflavonoid consumption on ERβ in men with organ-localized prostate cancer. We hypothesized that ERβ DNA promoter methylation would decrease in prostate cancer with soy isoflavonoid treatment and this would result in an increase in ERβ expression. DNA promoter methylation density of a gene is inversely correlated with the gene’s transcription and subsequent protein expression. During this 4 week, phase IIb, randomized, placebo-controlled clinical trial 62 men were randomized to receive 50 grams of protein/day composed of either 1) casein-lactalbumin protein (soy-free) or 2) soy protein containing a 100 mg/day dose of isoflavonoids. This dietary treatment resulted in an unexpected significant increase in promoter methylation of the ERα gene in the neoplastic epithelium and a 50% decrease in expression of the estrogen responsive gene, progesterone receptor, but no change in ERβ DNA promoter xi methylation or expression. These findings demonstrate that dietary soy isoflavonoid treatment can result in significant epigenetic changes in the promoter regions of sex steroid receptor genes in prostate cancer, alter sex steroid hormone receptor expression, and may restore expression of the two ERs to a ratio that more closely resembles that found in normal prostate epithelium.

subject

Prostate

Soy

Epigenetic

Estrogen

contributor

Perry, Donna L. (author)

Cramer, Scott (committee chair)

Cline, J. Mark (committee member)

Adams, Michael R. (committee member)

Register, Thomas C. (committee member)

Torti, Suzy V. (committee member)

Kaplan, Jay R. (committee member)

date

2009-12-17T13:24:40Z (accessioned)

2010-06-18T18:58:37Z (accessioned)

2009-12-17T13:24:40Z (available)

2010-06-18T18:58:37Z (available)

2009-12-17T13:24:40Z (issued)

degree

Molecular & Cellular Pathobiology (discipline)

identifier

http://hdl.handle.net/10339/14783 (uri)

language

en_US (iso)

publisher

Wake Forest University

rights

Release the entire work for access only to the Wake Forest University system for one year from the date below. After one year, release the entire work for access worldwide. (accessRights)

title

Dietary Soy Protein Isoflavonoid Effects on the Reproductive Tract of the Nonhuman Primate and Neoplastic Human Prostate Gland

type

Dissertation