Education:
- BS (1995) Animal Science. University of Massachusetts, Amherst, MA.
- DVM (2000). Mississippi State University, Starkville, MS.
- Residency: Anatomic Pathology (2000-2003) Cornell University, Ithaca, NY.
- Postdoctoral Fellowship in Comparative Medicine (2004-present) Wake Forest University School of Medicine.
Research Training:
Dr. Perry’s research, under the direction of Dr. Michael R. Adams, focuses on the role of diet in prostate cancer development, specifically if dietary intervention with soy-derived isoflavonoids can prevent or attenuate prostate cancer progression. Prostate cancer is the most common cancer diagnosed in men within the United States, second only to lung cancer as a cause of cancer-related death. Men that consume a diet rich in soy-derived protein, typically in Asian countries, have been reported to have one ninth the prostate cancer incidence of that reported in men that consume a traditional Western Diet. This epidemiological observation has prompted many to postulate that weakly estrogenic isoflavonoid isolates present in unadulterated soy proteins may have cytoprotective: anti-proliferative and pro-apoptotic effects in the prostate gland, preventing prostate cancer development and/or progression in populations that consume high concentrations of soy protein.
Several short-term pharmacokinetic studies evaluating the metabolism of soy isoflavonoids and several studies evaluating soy isoflavonoid effects on prostate specific antigen have been performed in men, though no long term studies evaluating the effects of continuous dietary soy isoflavonoid consumption on male reproductive tissues have been attempted. Dr. Perry is currently working on two parallel studies designed to evaluate the effects of long term (three year) dietary isoflavonoid supplementation on the reproductive tract of non-human primates and the effects of short term (4 week) dietary isoflavonoid supplementation on the prostate gland in men diagnosed with prostate cancer prior to radical prostatectomy.
The 31 month dietary isoflavonoid supplementation nonhuman primate arm of these two studies is of importance as several soy isoflavonoid dietary intervention studies in rodent models have reported adverse effects of soy-derived isoflavonoids on the prostate gland, demonstrating prostate gland atrophy. Following a continuous 31 month dietary soy isoflavonoid treatment, no significant deleterious effects of isoflavonoid supplementation were found histomorphometrically within the prostate gland, mammary gland, and no changes in sperm count were found within the testes in these male cynomolgus macaques (Macaca fascicularis) (Perry DL et al. J Nutr. 2007 Jun;137(6):1390-4).
Immunohistochemical detection and quantification of the cell cycle regulatory marker, p27, the proliferation markers, PCNA and Ki67 and the sex hormone receptor markers estrogen receptor alpha and beta, androgen receptor, and progesterone receptor within the prostate gland of these nonhuman primates have been performed. No significant differences in expression of proliferation markers or in the cell cycle regulatory marker p27of the prostatic epithelium were detected, though a significant increase in estrogen receptor beta was detected within the low soy protein treatment group.
Estrogen receptor beta, first described in 1996, is expressed in the epithelium of the prostate gland. The function of this epithelial expression is not completely elucidated, though several in vitro and in vivo studies have demonstrated that receptor activation through estrogen or soy isoflavonoid binding, has an antiproliferative effect in prostatic epithelial cells. Estrogen receptor beta expression is commonly decreased or lost in organ-localized, high Gleason Grade prostate tumor epithelium. The observation of estrogen receptor beta activation resulting in decreased proliferation and loss of receptor expression in high grade, organ localized prostate cancer has resulted in speculation that estrogen receptor beta may function as a tumor suppressor within the prostate gland. Estrogen receptor beta expression loss in prostatic adenocarcinoma has been demonstrated to be an epigenetic effect; the result of gene silencing secondary to promoter methylation of the estrogen receptor beta gene, rather than caused by gene inactivation secondary to mutation of the gene.
Gene silencing secondary to promoter methylation provides an opportunity for clinical intervention, as gene-re-expression can be induced by a variety of DNA demethylating agents. In vitro studies using prostate cancer cell lines have shown that soy isoflavonoids can reverse gene silencing caused by DNA promoter methylation. This gene re-expression with isoflavonoid treatment has been speculated to be due to inhibition of DNA methyltransferases, though the exact mechanism is not currently known.
The epidemiologic observation of lower prostate cancer mortality rates in men living in countries that consume high concentrations of soy protein and the observation that soy isoflavonoids may inhibit DNA methyltransferases, resulting in tumor suppressor gene re-expression has lead to our hypothesis that the lower prostate cancer incidence associated with soy protein isoflavonoid consumption may be the result of a combined gene/nutrient interaction. Specifically, the overarching hypothesis that estrogen receptor epigenetic silencing through DNA promoter methylation in neoplastic prostatic epithelial cells can be reversed by dietary soy isoflavonoids when given at physiologically achievable levels, as shown by a positive correlation between serum and/or intraprostatic isoflavonoid concentrations and estrogen receptor beta expression and an inverse correlation with neoplastic cell proliferation.
A major criticism of most dietary soy isoflavonoid supplementation studies is that dietary supplementation cannot result in serum or tissue concentrations that are high enough to have a physiologic effect. Interestingly, soy isoflavonoids have been demonstrated to concentrate in prostate tissue at concentrations four fold to twenty-three fold higher than those found in serum, sometimes reaching the micromolar level.
The second short term (4 week) dietary soy intervention study in men (n=62) diagnosed with prostate cancer is currently underway and the tissue collected during the course of that study will be utilized to examine this gene/nutrient interaction through the following specific aims:
- To determine intra-prostatic soy isoflavonoid concentrations and compare these concentrations to those measured in the serum.
Hypothesis: Soy isoflavonoids will concentrate within the prostate gland tissue at levels 4-23 fold above those found in the serum.
- To determine estrogen receptor beta DNA promoter CpG island methylation within neoplastic prostate tissue collected from men treated with soy protein containing isoflavonoids and men receiving casein lactalbumin (animal-derived) protein.
Hypothesis: Estrogen receptor beta promoter CPG island methylation will be decreased within prostatic tissue in men treated with soy protein containing isoflavonoids when compared to those receiving a similar concentration of casein lactalbumin-derived protein.
- Correlate intra-prostatic soy isoflavonoid concentrations with estrogen receptor beta DNA promoter methylation data and estrogen receptor beta protein expression data in tissue using immunohistochemical marker and cell proliferation and apoptosis.
Hypothesis: Soy isoflavonoids will concentrate in prostatic tissue resulting in a reduction in estrogen receptor beta DNA promoter methylation decreasing prostate cancer cell proliferation and increasing apoptosis.
Presentations and Awards:
February, 2005. Poster Presentation. 14th Annual Meeting of the Triangle Consortium for Reproductive Biology, UNC School of Medicine, Chapel Hill, NC. "The Histopathologic Effects of Soy-Derived Isoflavones on the Prostate Gland."
October, 2005. Poster Presentation. 6th International Symposium on the Role of Soy in Preventing and Treating Chronic Disease, Chicago, IL. "Dietary Soy Isoflavones Have No Adverse Effects on the Nonhuman Primate Prostate, Testis, or Mammary Gland."
December, 2005. Poster Presentation - Christopher T. Starost Memorial Oncology Scholarship Second Place Award. 56th Annual Meeting of the American College of Veterinary Pathologists, Boston, MA. "The Effects of Polyunsaturated Fatty Acids on Prostatic Adenocarcinoma Development in the Prostate-Specific PTEN Knockout Murine Model."
Grants:
November 2007 - 2010. Department of Defense (DOD) Prostate Cancer Research Program (PCRP) Prostate Cancer Training Award from the Office of the Congressionally Directed Medical Research Programs (CDMRP).
February 2008: Department of Pathology at Wake Forest University School of Medicine Intramural Grant.
Publications:
Perry DL, Spedic JM, McCoy TP, Adams MR, Franke AA, Cline JM. Dietary soy protein containing isoflavonoids does not adversely affect the reproductive tract of male cynomolgus macaques (Macaca fascicularis). J Nutr. 2007 Jun;137(6):1390-4.
Berquin IM, Min Y, Wu R, Wu J, Perry D, Cline JM, Thomas MJ, Thornburg T, Kulik G, Smith A, Edwards IJ, D’Agostino R, Zhang H, Wu H, Kang JX, Chen YQ. Modulation of prostate cancer genetic risk by omega-3 and omega-3 fatty acids. J Clin Invest 117(7):1866-1875.