Androgen Receptor Roles in the Development of Benign Prostate Hyperplasia

Benign prostate hyperplasia (BPH) is a major cause of lower urinary tract symptoms, with an increased volume of transitional zone and associated with increased stromal cells. It is known that androgen/androgen receptor (AR) signaling plays a key role in development of BPH, and that blockade of this signaling decreases BPH volume and can relieve lower urinary tract symptoms, but the mechanisms of androgen/AR signaling in BPH development remain unclear, and the effectiveness of current drugs for treating BPH is still limited. The detailed mechanisms of androgen/AR signaling need to be clarified, and new therapies are needed for better treatment of BPH patients. This review focuses on roles of AR in epithelial and stromal cells in BPH development. In epithelial cells, AR may contribute to BPH development via epithelial cell–stromal cell interaction with alterations of epithelial–mesenchymal transition, leading to proliferation of stromal cells. Data from several mouse models with selective knockout of AR in stromal smooth-muscle cells and/or fibroblasts indicate that the AR in stromal cells can also promote BPH development. In prostatic inflammation, AR roles in infiltrating macrophages and epithelial and stromal cells have been linked to BPH development, which has led to discovery of new therapeutic targets. For example, targeting AR with the novel AR degradation enhancer, ASC-J9 offers a potential therapeutic approach against BPH development.Benign prostatic hyperplasia (BPH) is the most common male benign proliferative disease, and approximately 8 million patients are estimated to visit physicians with the diagnosis of primary or secondary BPH.¹ The incidence of gross enlargement of the prostate gland has been reported as 40% in 70-year-old men, and microscopic foci of the prostate gland are present in up to 80% of these men.² BPH patients often have lower urinary tract symptoms, and need to be treated with surgery or medication. Although transurethral resection of the prostate is the most common surgical treatment for BPH worldwide, the procedure can lead to complications (eg, bleeding, urethral stricture, incontinence) and may have limitations for people of advanced age.^3–5 Although α-blockers are frequently prescribed for treatment of BPH and have a quick onset of action, within 3 to 5 days,⁶ these drugs alone fail to shrink BPH volume and are often insufficient to eliminate symptoms.⁷ In contrast, 5-α reductase inhibitors (5-ARIs), which suppress testosterone conversion into dihydrotestosterone (DHT), have greater efficacy in reducing BPH volume, and clinical data indicate that the combination of 5-ARIs with α-blockers leads to the best symptomatic response to date.^8,9The above clinical data suggest that androgen/androgen receptor (AR) signaling plays key roles in development of BPH and that targeting androgen/AR signaling could be a major therapeutic approach for BPH. Nevertheless, the detailed mechanisms of androgen/AR signaling, and especially the pathogenic roles of AR in BPH,¹⁰ are still unclear.In this review, we focus on the roles of AR in promoting prostate stromal cell growth¹¹ and prostate epithelial cell growth with increased epithelial–mesenchymal transition (EMT).¹² We also discuss how AR regulates development of BPH through the inflammatory environment with macrophage infiltration, and address potential new therapeutic approaches, such as targeting AR with the newly identified AR degradation enhancer ASC-J9 and/or targeting specific inflammatory cytokines downstream of AR.     

Stromal Androgen Receptor in Prostate Development and Cancer

The androgen receptor (AR) in stromal cells contributes significantly to the development and growth of prostate during fetal stages as well as during prostate carcinogenesis and cancer progression. During prostate development, stromal AR induces and promotes epithelial cell growth, as observed from tissue recombinant and mouse knockout studies. During prostate carcinogenesis and progression, the stromal cells begin to lose AR expression as early as at the stage of high-grade prostatic intraepithelial neoplasia. The extent of loss of stromal AR is directly proportional to the degree of differentiation (Gleason grade) and progression of prostate cancer (PCa). Co-culture studies suggested that stromal AR inhibits the growth of malignant epithelial cells, possibly through expression of certain paracrine factors in the presence of androgens. This functional reversal of stromal AR, from growth promotion during fetal prostate development to mediating certain growth-inhibiting effects in cancer, explains to some extent the reason that loss of AR expression in stromal cells may be crucial for development of resistance to androgen ablation therapy for PCa. From a translational perspective, it generates the need to re-examine the current therapeutic options and opens a fundamental new direction for therapeutic interventions, especially in advanced PCa.CME Accreditation Statement: This activity (“ASIP 2014 AJP CME Program in Pathogenesis”) has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Society for Clinical Pathology (ASCP) and the American Society for Investigative Pathology (ASIP). ASCP is accredited by the ACCME to provide continuing medical education for physicians.The ASCP designates this journal-based CME activity (“ASIP 2014 AJP CME Program in Pathogenesis”) for a maximum of 48 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.CME Disclosures: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose.Prostate cancer (PCa) is the most common non-skin malignancy in the male population within the United States and is the second most common cancer in men worldwide.¹ It is also one of the leading causes of cancer-related deaths in males in the United States.Normal human prostate is composed of an epithelial tissue and an adjacent stroma. The epithelium is composed of two principal cell types, the tall columnar secretory luminal cells that line the glandular ducts and the flattened basal cells surrounding them. In addition, some rare neuroendocrine cells are also present. Often, the terms mesenchyme and stroma are loosely used. Herein, mesenchyme refers to the mesodermal-derived fetal or newborn tissues with instructive induction potential. The word stroma describes the tissues surrounding the prostatic epithelium, later in development. In the adult human prostate, the stroma is composed mainly of smooth muscle cells. However, it also includes some fibroblasts, nerves, blood vessels, and various infiltrating immune and inflammatory cell types.Circulating androgens mediate the development and function of prostate by stimulating the androgen receptor (AR). Rat studies have shown that in stroma, AR is expressed in mesenchymal cells of the urogenital sinus (UGS), especially those adjacent to the epithelium, concurrent with the formation of prostatic buds.^2,3 As the prostate develops and the mesenchymal cells differentiate to form smooth muscle, AR expression is widespread, but not universal, throughout the muscle. In the past, investigators have mainly focused on studying epithelial AR function in prostate. Relatively limited data are available to describe the expression and function of stromal AR in prostate development^2–14 and cancer. Stromal AR is involved in both prostate development and prostate carcinogenesis, with distinct functions in these two processes. We examine the current knowledge and understanding of stromal AR function, including its translational significance.     

The Differential Expression and Function of the Inflammatory Chemokine Receptor CXCR5 in Benign Prostatic Hyperplasia and Prostate Cancer

Background: Chemokine and chemokine receptors could have played an important role in tumor angiogenesis and distant metastasis. The mechanism of inflammation, expression and function of chemokines and chemokine receptors in benign prostatic hyperplasia (BPH) and prostate cancer (PCa) remain unclear. The purpose of present study is to detect differential expression and function of chemokines and chemokine receptors (CCRs) in BPH and PCa.Methods: BPH-1 and peripheral blood mononuclear cells (PBMCs) were co-cultured in Transwell chambers, and human normal prostate (NP) tissues, BPH tissues and PCa tissues were collected. CCR gene-chips were used to analyze and compare the differential expression of CCRs in BPH-1 cells, BPH-1 cells co-cultured with PBMCs, and LNCaP cells. The differential expression of CCRs was detected and validated using real-time PCR, western blotting and immunofluorescence (IF). The proliferation of LNCaP cells was also investigated after the knockdown CXCR5.Results: Results of gene-chips indicated that there was low or no expression of CCR10, CXCR1, CXCR3 and CXCR5 in BPH-1 cells, whereas the expression of these receptors in BPH-1 cells was increased by PBMCs, and the expression was high in LNCaP cells. Furthermore, real-time PCR and western blotting confirmed the above mentioned results. IF verified no or low expression of CXCR1, CXCR3 and CXCR5 in NP tissues, low or moderate expression in BPH and high expression in PCa. However, CCR10 was not expressed at detectable levels in the three groups. The growth and proliferation of LNCaP cells was markedly inhibited after down-regulation of CXCR5.Conclusions: PCa cells expressed high levels of CCR10, CXCR1, CXCR3 and CXCR5. Although BPH cells did not express these factors, their expression was up-regulated when BPH-1 cells were incubated with inflammatory cells. Finally, down-regulation of CXCR5 inhibited the growth and proliferation of LNCaP cells.     

雄激素受体异常激活与激素非依赖性前列腺癌的形成机制

前列腺癌进展的晚期常转变为激素非依赖性 ,包括雄激素受体拮抗剂在内的多种细胞外因子能够刺激其增殖。雄激素受体基因突变、多种途径引起的异常磷酸化激活和共激活物的调节失控等是激素非依赖性前列腺癌形成的主要促成因素。以雄激素受体为靶标可能成为晚期前列腺癌的有效治疗途径。     

乳酸脱氢酶在前列腺增生与前列腺癌中的分析

目的 探讨乳酸脱氢酶在前列腺增生与前列腺癌患者血清中的表达情况,在前列腺穿刺活检或手术前的诊断价值.方法 回顾性分析2018年1月至2021年3月就诊于首都医科大学附属北京世纪坛医院进行前列腺手术或穿刺活检患者临床资料,按照纳入及排除标准,最终选择262例患者,其中前列腺癌89例,前列腺增生患者173例.以病理结果为诊断标准,使用SPSS 21.0软件进行数据分析处理,比较前列腺癌与前列腺增生组间乳酸脱氢酶表达水平,并分析疾病诊断风险因素,绘制受试者工作曲线(receiver operating characteristic curve,ROC),分析术前乳酸脱氢酶对于前列腺癌疾病预测的诊断价值.结果 乳酸脱氢酶在前列腺癌血清中表达水平显著高于前列腺增生患者,差异具有统计学意义(P<0.05).单变量Logistic回归研究发现术前血清乳酸脱氢酶(P=0.010)是预测前列腺癌的独立危险因素之一.将乳酸脱氢酶用于前列腺癌诊断,其曲线下面积为0.610,约登指数最高时乳酸脱氢酶截止值为173.5 U/L时,特异性为72.3％,灵敏度为50.6％.结论 血清乳酸脱氢酶对于前列腺癌有一定诊断价值,可以作为前列腺疾病辅助诊断指标之一.     

兰州地区前列腺增生和前列腺癌发病情况及发病因素分析

为了解兰州地区前列腺增生 (BPH)和前列腺癌的发病情况 ,调查了该地区 5 0岁以上男性 135 6人的国际前列腺症状评分 (I-PSS)、生活质量评分 (L)、前列腺体积 (V)、直肠指检等情况 ,测量了 14 5人血清睾酮 (T)、前列腺特异抗原 (PSA)。结果显示 ,BPH发病率占总调查人数的 35 .0 3% (4 75 / 135 6 ) ,城市人口发病率 4 1.0 4 %(2 5 2 / 6 14 ) ,农村人口发病率 30 .0 5 % (2 2 3/ 74 2 ) ;城市人口明显高于农村 (P <0 .0 5 )。前列腺癌占总调查人数的2 .5 0 % (34/ 135 6 ) ;城市职工 3.0 9% ,农村人口 2 .0 2 % ;城市人口同样高于农村人口。前列腺癌组PSA明显高于正常对照组 (P <0 .0 5 )。结论 :城镇职工的BPH和前列腺癌的发病率高于农村人口 ,与年龄、城乡地区、饮食结构有关 ,已成为常见的老年病     

诱导型一氧化氮合酶在正常前列腺、良性前列腺增生及前列腺癌组织中的表达研究

目的：探讨诱导型一氧化氮合酶（iNOS）与良性前列腺增生（BPH）、前列腺癌（PCa）病理生理变化的关系。方法：采用免疫组化方法检测6例正常前列腺组织、15例BPH患者的前列腺组织以及9例前列腺癌组织中iNOS的表达。结果：BPH组与PCa组中iNOS呈阳性表达，主要分布于前列腺上皮细胞及前列腺癌细胞胞浆内，间质平滑肌细胞内及正常前列腺组织内均未见表达，iNOS在PCa组织中的表达低于BPH组（P〈0．05）。结论：iNOS产生的NO在BPH及前列腺癌的发生发展过程中起重要作用，但iNOS在前列腺肿瘤发病机制的确切作用还需进行进一步研究。     

The Expression of the Androgen Receptor and Estrogen Receptor 1 is Related to Sex Dimorphism in the Gerbil Prostate Development

The development of the prostate gland in females has not yet been clearly elucidated, and the sexual dimorphism associated with such gland development in general is far from being understood. In the present study, we used tridimensional (3D) reconstructions and histochemical and immunohistochemical techniques to describe the sexual dimorphism and its causes in the early postnatal development of the prostate in male and female Mongolian gerbils (Meriones unguiculatus). We observed that the female prostate was smaller, had fewer branches throughout the development, and underwent differentiation earlier than that in males. Also, the expression of the estrogen receptor 1 (ESR1 or ER‐alpha) and fibroblast growth factor 10 (FGF10) was decreased in the periductal region, and the expression of the androgen receptor (AR) was increased in the epithelium. All together, these changes decreased proliferation and branching and led to an earlier prematuration of the female prostate. These new data shed light on the underlying mechanisms involved with the sexual dimorphism in the development of the prostate. Anat Rec, 299:1130–1139, 2016. © 2016 Wiley Periodicals, Inc.     

Infrared Microspectroscopic Detection of Epithelial and Stromal Growth in the Human Benign Prostatic Hyperplasia

Benign prostatic hyperplasia (BPH) is one of the most common diseases in elderly men. It describes an overgrowth of the epithelial and fibromuscular tissues in the human prostate, in which both epithelium and stroma continue to proliferate at different rates. There is lack of suitable techniques for direct evaluation of the biophysical structure of molecular constituents and the proliferative changes in the structure of both compartments at the microscopic level. Reflectance Fourier transform infrared (FT-IR) microspectroscopy was used to pathologically image and examine the structural changes in the proliferation of epithelial and stromal tissues of human BPH. Two successive thin tissue slices were obtained by cutting the tissue with a microtome: one unstained slice was used for FT-IR spectroscopic analysis and the other stained slice was used for position referencing. The result indicates that the amide I maximum for BPH epithelial tissue was near 1,638 cm -1 and showed its protein secondary structure by a combination of unordered and &#103 -sheet structures. However, an intense absorption band of amide I was at 1,630 cm -1 for stromal BPH tissue due to the predominant &#103 -sheet structure. The higher peak intensity of several IR bands at 1,337, 1,281, 1,238, 1,206, 1,055, and 1,034 cm -1, assigned to the C-O stretching mode of collagen, was observed in BPH stromal tissue. This suggests that the obvious collagen will be more enriched in the stroma of BPH tissue.     

New Therapeutic Approach to Suppress Castration-Resistant Prostate Cancer Using ASC-J9 via Targeting Androgen Receptor in Selective Prostate Cells

Using androgen receptor (AR) knockout mice to determine AR functions in selective prostate cancer (PCa) cells, we determined that AR might play differential roles in various cell types, either to promote or suppress PCa development/progression. These observations partially explain the failure of current androgen deprivation therapy (ADT) to reduce/prevent androgen binding to AR in every cell. Herein, we identified the AR degradation enhancer ASC-J9, which selectively degrades AR protein via interruption of the AR-AR selective coregulator interaction. Such selective interruption could, therefore, suppress AR-mediated PCa growth in the androgen-sensitive stage before ADT and in the castration-resistant stage after ADT. Mechanistic dissection suggested that ASC-J9 could activate the proteasome-dependent pathway to promote AR degradation through the enhanced association of AR-Mdm2 complex. The consequences of ASC-J9-promoted AR degradation included reduced androgen binding to AR, AR N-C terminal interaction, and AR nuclear translocation. Such inhibitory regulation could then result in suppression of AR transactivation and AR-mediated cell growth in eight different mouse models, including intact or castrated nude mice xenografted with androgen-sensitive LNCaP cells or androgen-insensitive C81 cells and castrated nude mice xenografted with castration-resistant C4-2 and CWR22Rv1 cells, and TRAMP and Pten^+/− mice. These results demonstrate that ASC-J9 could serve as an AR degradation enhancer that effectively suppresses PCa development/progression in the androgen-sensitive and castration-resistant stages.Androgen/androgen receptor (AR) signaling plays essential roles in prostate cancer (PCa) progression and results in castration resistance.^1–4 Currently, most, if not all, androgen deprivation therapy (ADT) targets androgens via surgical and/or medical castration to reduce/prevent androgen binding to AR.⁵ However, few, if any, of these ADTs with various antiandrogens, including the recently developed enzalutamide,⁶ have the capacity to eliminate all PCa cells in the later castration-resistant stage. Therefore, degradation of AR during/after ADT can be considered to have clinical benefits for patients with advanced PCa with substantial AR.⁶ These conclusions suggest that identifying a novel compound(s) that could degrade/diminish AR protein in the castration-resistant stage, unlike currently used antiandrogens, may yield better therapeutic efficacies to battle PCa in the castration-resistant stage.Early studies via isolation of three PCa primary cells (PCa1, PCa2, and PCa3) from the same patient found that androgen/AR signaling could function differentially to either suppress or promote PCa growth.⁷ Using the cre-loxP strategy in mice to selectively knockout AR in various PCa cells, Niu and colleagues^3,4,8 observed that the loss of AR in cytokeratin 5/cytokeratin 8–positive basal intermediate epithelial cells led to increased PCa metastasis, yet loss of AR in cytokeratin 8–positive luminal epithelial cells resulted in suppressed PCa progression with increased cell apoptosis. In contrast, loss of AR in stromal fibroblasts and smooth muscle cells resulted in suppression of prostate/PCa growth.^9,10 These results conclude that AR can either promote or suppress PCa progression in different types of PCa cells.Because only one AR gene has been identified,¹¹ we hypothesized that these differential AR roles in various PCa cells in the same patient could be due to the existence of different AR-AR coregulator complexes. This hypothesis led us to screen the AR degradation enhancer 5-hydroxy-1,7-bis(3,4-dimethoxyphenyl)-1,4,6-heptatrien-3-one (ASC-J9) from natural products and their derivatives by selectively interrupting the interaction between AR and selective AR coregulators, such as AR–AR-associated protein (ARA) 70 and AR-ARA55, which are expressed mainly in luminal epithelial cells and stromal cells, respectively, in which AR may function with positive roles to either maintain cell survival or promote cell proliferation. Results from four different human PCa cell lines and eight different in vivo mouse models concluded that ASC-J9 could function as a promising AR degradation enhancer to suppress PCa progression before and after castration resistance with few adverse effects.     

Evaluation of Molecular Species of Prostate-Specific Antigen Complexed with Immunoglobulin M in Prostate Cancer and Benign Prostatic Hyperplasia

This study was aimed at defining molecular species of prostate-specific antigen (PSA) in immune complexes with immunoglobulin M (IgM). Having in mind the oligoreactivity of IgM and its preference for carbohydrate antigens, there is the possibility that it can selectively recognize known PSA glycoisoforms. PSA-IgM complexes and free PSA fractions were separated from the sera of subjects with prostate cancer (PCa) and benign prostatic hyperplasia (BPH) by gel filtration and subjected to on-chip immunoaffinity and ion-exchange chromatography. PSA-immunoreactive species were detected using surface-enhanced laser desorption/ionization time of flight mass spectrometry. The obtained spectra were analyzed for protein and glycan composition. The general pattern of the molecular species of PCa PSA and BPH PSA found in complexes with IgM was similar. It comprised major peaks at 17 kDa and minor peaks at 28 kDa, corresponding to the entire mature glycosylated PSA. The main difference was the presence of incompletely glycosylated 26.8 kDa species, having putative paucimannosidic structures, observed in PCa PSA-IgM, but not in BPH PSA-IgM. Characteristic PCa PSA-IgM glycoforms pose the question of the possible role of glycosylation as a framework for immune surveillance and may be of interest in light of recent data indicating mannose-containing glycans as cancer biomarker.     

汽化电切术治疗合并糖尿病的前列腺增生症

目的：评价经尿道汽化电切术（TVP）治疗合并糖尿病的前列腺增生症（BPH）的临床效果。方法：采用TVP治疗合并糖尿病的前列腺增生症24例。结果：本组23例治疗满意;1例术后尿潴留者,经腹直肌转位术治疗后,能自行排尿。24例术后3个月复查,残余尿量明显减少,最大尿流率（Qmax）由手术前（6.7±1.8）mL/s到术后（17.9±2.6）mL/s。无电切综合征（TURS）及死亡病例。结论：TVP是治疗BPH合并糖尿病的可行方法。     

Exploring the Origins of the Normal Prostate and Prostate Cancer Stem Cell

Prostate epithelial stem cells (PSCs) are primed by the urogenital mesenchyme to initiate bud formation and branching morphogenesis, ultimately culminating in a glandular structure composed of luminal, basal and neuroendocrine cells. Identity of this cell has remained elusive however cell populations enriched for cells exhibiting stem cell characteristics express the stem cell markers CD133⁺, α2β1^hi, CD44 and Sca-1 along with embryonic stem cell factors including Oct-1, Nanog, Sox2 and nestin. Androgens are critical to prostate organogenesis and play a major role in normal prostate function and the development of prostate cancer. Cell lineage is another variable in the development of prostate cancer. This review discusses the embryonic prostate stem cell niche, normal prostate development, isolation and characterization of normal prostate and prostate cancer stem cells, and current concepts on the origin of prostate cancer. Funding for this work was provided by the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK60957) and the Frances Williams Preston Laboratories of the T.J. Martell Foundation. An erratum to this article can be found at     

Suppressive Roles of Calreticulin in Prostate Cancer Growth and Metastasis

Calreticulin is an essential, multifunctional Ca²⁺-binding protein that participates in the regulation of intracellular Ca²⁺ homeostasis, cell adhesion, and chaperoning. Calreticulin is abundantly expressed and regulated by androgens in prostate epithelial cells. Given the importance of both calreticulin in multiple essential cellular activities and androgens in prostate cancer, we investigated the possibility of a role for calreticulin in prostate cancer progression. Immunohistochemistry revealed the down-regulation of calreticulin in a subset of human prostate cancer specimens. Prostate cancer cells overexpressing exogenous calreticulin produced fewer colonies in both monolayer culture and soft agar. Furthermore, calreticulin overexpression also inhibited tumor growth in the orthotopic PC3 xenograft tumor model and macroscopic lung metastasis in the rat Dunning AT3.1 prostate tumor model. To address the potential mechanism of calreticulin suppression of prostate cancer, we generated calreticulin mutants with different functional domains deleted. The calreticulin mutants containing the P-domain, which binds to other endoplasmic reticulum chaperone proteins, were sufficient for the suppression of PC3 growth in colony formation assays. Overall, our data support the hypothesis that calreticulin inhibits growth and/or metastasis of prostate cancer cells and that this suppression requires the P-domain.Prostate cancer was the most frequently diagnosed non-skin cancer and the third leading cause of cancer death among American men in 2008.¹ Androgens are intimately associated with prostate cancer progression and as such, androgen ablation remains the standard therapy for patients with metastatic prostate cancer.² However, hormone therapy is not curative and the vast majority of treated patients eventually experience disease progression. Elucidating the mechanism of androgen influence on prostate cancer is important as it may facilitate the development of more effective therapies and methods of disease prevention.Androgen action is mediated through the androgen receptor, which controls the expression of androgen-responsive genes.³ As androgen-responsive genes likely play important roles in prostate cancer progression, the characterization of their expression patterns and functions should provide insight into the roles of androgen in disease development. Calreticulin is one of the androgen-responsive genes in the prostate.^4,5 Androgen ablation by castration rapidly down-regulates calreticulin at both the mRNA and protein levels by more than tenfold. In contrast, androgen replacement rapidly restores the expression of calreticulin in the regrowth of the castrated prostate. Northern blot analysis of the tissue-specificity of calreticulin expression in the rat model shows that the most abundant levels occur in the prostate, as compared with the liver, kidney, brain, heart, muscle, and seminal vesicles. In situ hybridization and immunohistochemistry studies demonstrate that prostatic epithelial cells specifically express calreticulin.^5,6 The expression profile and androgen-responsiveness of calreticulin in the prostate indicate that calreticulin may play a key role in androgen action in prostate epithelial cells.Calreticulin performs a variety of functions within the cell. This evolutionarily conserved protein localizes to the endoplasmic reticulum (ER),^7,8,9 but possibly may also be found at the cell surface.^10,11 Within the ER, calreticulin serves as a molecular chaperone to ensure proper folding of glycoproteins.^12,13,14,15 In addition, calreticulin modulates intracellular Ca ²⁺ homeostasis by its ability to bind Ca²⁺ with high affinity.^6,16,17,18 Other possible activities include integrin α-binding and cell adhesion,^19,20,21,22 major histocompatibility class I assembly,²³ steroid-mediated gene regulation,^24,25,26 as well as Zn²⁺ binding and storage.²⁷ Gene knockout experiments further underscore the importance of this protein, as loss of calreticulin results in embryonic death from defective cardiac development.²⁸ Calreticulin consists of three distinctive domains. The N-domain (residues 1 to 180) is thought to bind heavy metals (Zn²⁺) and interact with other ER chaperones, nuclear receptors, and nucleic acids.²⁹ The P-domain (residues 181 to 290) contains a proline-rich region that forms an extended arm structure and interacts with other chaperones in the lumen of the ER. Lastly, the C-domain (residues 291 to 400) is a highly acidic region that binds Ca²⁺ and is involved in Ca²⁺ storage.³⁰Although the role of calreticulin in normal cellular functions and during embryogenesis is well-established, its role in human carcinogenesis remains poorly understood.³¹ In the current study, we demonstrate the down-regulation of calreticulin protein in a subset of human prostate cancer specimens. Furthermore, we show that calreticulin overexpression in prostate cancer cells inhibits prostate tumor growth and metastasis and that its growth inhibitory role requires the P-domain. Overall, our present study provides evidence, for the first time, that calreticulin is capable of suppressing prostate cancer progression.