Original Article Genotyping of Sex Hormone-Related Pathways in Benign and Malignant Human Prostate Tissues: Data of a Preliminary Study Carmela Rita Balistreri, 1 Calogero Caruso, 1 Giuseppe Carruba, 1,2 Vitale Miceli, 1,2 and Giuseppina Candore 1 Abstract Prostate cancer (PCa) is a major health issue in Westernized countries, representing a common cause of morbidity and mortality in the elderly male population. Endogenous sex steroids, along with environmental factors (notably diet) and host immune and inflammatory responses, are likely to cooperate in the pathogenesis of the disease. Based on the assumption that a complex endocrine–inflammatory-immune interaction is primarily implicated in human PCa, we have investigated the interplay between sex steroids and inflammation in development and growth of human PCa. To this end, we have assessed nine functional single nucleotide polymorphisms (SNP)s of five genes involved in sex hormone-related pathways in both hyperplastic and malignant human prostate tissues, as well as in matched controls and in a ‘‘supercontrol’’ group composed of male Sicilian centenarians. In par- ticular, the following genes were investigated: AR-OMIM313700, SRD5A2-NM-000348, CYP19-NM-031226, ERS1-NM-001122742, ERS2-NM-001040276. A significant association with prostate cancer was found in seven out of the nine SNPs considered. Although this is a preliminary study and larger investigations are needed to confirm the role of these genes in PCa development and/or progression, our data might provide an experimental basis to develop additional or alternative strategies for prevention and treatment of PCa. Introduction S ex steroid hormones are generally believed to play a critical role in the complex pathophysiology of human PCa (Caruso et al., 2009; Ellem and Risbridger, 2010; Ricke et al., 2007). Androgens are primarily responsible for devel- opment and function of human prostate gland, as well as for the maintenance of homeostasis of prostate tissues in the adulthood. The major prostatic androgens are the testosterone and its derivative dihydrotestosterone, produced locally through the 5a-reductase enzyme. Most of their effects are mediated by binding to androgen receptors (AR). Androgens also represent well-established risk factors for development and progression of benign and malignant disorders of pros- tate gland (Ricke et al., 2007). Today there is accumulating evidence suggesting that es- trogens play a crucial role in both normal and diseased human prostate (Carruba, 2007; Ellem and Risbridger, 2009, 2010; McPherson et al., 2008). In particular, a combined action of androgens and estrogens and their balance appear to be crit- ically important in maintaining prostate health and tissue homeostasis. An alteration of this balance has been recently implicated in the development of both benign and malignant diseases, including PCa (Ellem and Risbridger, 2009, 2010). Aging men have unchanged or increased circulating levels of estradiol, as opposed to the decline of plasmatic testoster- one. Estrogen production is maintained through aromatiza- tion of adrenal androgens driven by the aromatase enzyme, especially in peripheral adipose tissue (Ellem and Risbridger, 2010). In normal prostate gland, the aromatase enzyme is expressed within the stroma, while the malignant prostate show an aberrant aromatase expression in the epithelial compartment (Ellem and Risbridger, 2010). This withdraws circulating testosterone and results in a significant reduction of plasma testosterone to estradiol ratio that has been asso- ciated to an increased risk of developing PCa (Carruba, 2007). The estrogen role in human prostate is further compli- cated by the differential expression and activity of the two estrogen receptors (ER), a and b (Ellem and Risbridger, 2009, 2010). A sustained activation of ERa may eventually lead to an aberrant proliferation, inflammation and to development of premalignant lesions. In contrast, ERb appears to have 1 Immunosenescence Group, Department of Pathobiology and Medical and Forensic Biotechnologies, University of Palermo, Palermo, Italy. 2 Experimental Oncology, Department of Oncology, ARNAS-Civico, Palermo, Italy. OMICS A Journal of Integrative Biology Volume 15, Number 0, 2011 ª Mary Ann Liebert, Inc. DOI: 10.1089/omi.2010.0128 1 OMI-2010-0128-Balistreri_1P OMI-2010-0128-Balistreri_1P.3D 12/27/10 11:57am Page 1