Prostate Cancer Is The Second Most Frequent Biology Essay

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Prostate cancer is the second most frequently diagnosed cancer in males worldwide, and the most frequent cancer in economically developed countries. It accounted for 14% (903,500) of the total new cancer cases and 6% (258,400) of the total cancer deaths in males world-wide in 2008 [1]. In the United States, prostate cancer accounts for 29% (241,470) of expected new cancer cases and 9% (28,170) of cancer deaths in males in 2012 [2]. Among the well-established risk factors for prostate cancer are age, ethnic background, and family history [3, 4]. About 60% of men diagnosed with prostate cancer are >70 years old. Males of African descent in the Caribbean region have the highest prostate cancer mortality rates in the world [3, 5-7]. A positive family history of prostate cancer is one of the strongest risk factors. In first-degree relatives of affected men, the relative risk of prostate cancer is about 2-fold higher, and the risk is much higher when they are diagnosed at younger ages [8-10].

The familial clustering (aggregation) of prostate cancer and breast cancer has been observed for almost half a century. A family history of breast cancer significantly increases the risk of the prostate cancer in men [11-14]. In 1993, an Icelandic study found a higher risk of prostate cancer in families with multiple breast cancer cases, and haplotype analysis proved its association with the breast cancer susceptibility gene BRCA1 (breast cancer 1, early onset) [15]. Germ-line mutations of BRCA1 and BRCA2 (breast cancer 2, early onset) have been found to account for 85% of hereditary (inherited) breast cancer (5-10% of total breast cancer) [16-20]. Among the sporadic breast cancers, 30-40% of cases have lower BRCA1/2 expression [20-24], frequently due to the loss of heterozygosity (LOH) and hypermethylation-mediated silencing of these two genes [25-27]. Other studies have examined germ-line mutations of BRCA1/2 in prostate cancer patients. It has been reported that the relative risk of prostate cancer in male BRCA1 mutation carriers is 2-3 fold increased, with a lifetime risk up to 30% [28, 29], and male BRCA2 mutation carriers have a 5-23-fold increase of prostate cancer ≤ 55 years age [30] and the lifetime risk is 19%-34% [31-33]. The contribution of BRCA2 germ-line mutations to prostate cancer risk is relatively clear, whereas the association of BRCA1 mutations and prostate cancer has been controversial in various ethnic groups [28, 32, 34]. Up to now, no study conducted rules out BRCA1 as a contributor to prostate cancer risk in families.

BRCA1 (Chr17q21.31) and BRCA2 (Chr13q12.3) are tumor suppressor genes, mainly involved in the DNA repair process. Recently, BRCA1 and BRCA2 have been shown to act as prostate cancer suppressors, interacting with the AR, JAK, IGFR, Skp2, MMP-9 and PI 3-kinase/AKT and MAPK/ERK signaling pathways. Mice with a conditional knock-out of the Brca2 gene in prostate epithelia demonstrate focal hyperplasia and low-grade prostate intraepithelial neoplasia (PIN) [35]. Loss of BRCA1 induces GADD153-mediated doxorubicin resistance in prostate cancer [36]. Here we review the recent advances about the role of BRCA1 and BRCA2 in prostate cancer, discussing both clinical relevance and basic research. This information might be helpful for genetic counselors, medical professionals, and prostate cancer patients and their family, when discussing prostate cancer risks, treatment options and prognosis for men in these susceptible families.

We used the HUGO Genome Nomenclature Committee (HGNC) nomenclature for BRCA1 (Genbank: U14680, RefSeq: NM_007294) and BRCA2 (U43746, NM_000059) variants in this review, as recommended by the Human Genome Variation Society (HGVC). The Breast cancer Information Core (BIC) nomenclature, which represents the largest repository of cases were referenced in parallel. The BRCA1 gene has 24 exons encoding a protein of 1,863 amino acids, and the BRCA2 gene has 27 exons encoding a protein of 3,418 amino acids. The name of BRCA1/2 variants begins with c. (see below) in the HGNC nomenclature, which stands for a coding DNA sequence (transcript).

Three common founder allelic variants have been found in the Ashkenazi Jewish population, BRCA1 gene c.66_67delAG (185delAG) and c.5263_5264insC (5382insC), and BRCA2 gene c.5946delT (6174delT) [37-39]. BRCA1 c.66_67delAG was first found in Ashkenazi Jewish breast cancer patients, and the frequency distribution in the general Ashkenazi Jewish population is ~ 1% [40]. This variant has also been found in the non-Ashkenazi Jewish, Spanish and United Kingdom (Yorkshire) populations [41, 42].

For prostate cancer, BRCA2 c.5946delT was found to be significantly associated with an increased risk of prostate cancer in Ashkenazi Jews. In a large-scale case control study, 251 unselected Ashkenazi prostate cancer patients and 1472 male healthy controls were enrolled [43]. The above three founder mutations of BRCA1/2 genes were detected. Thirteen (5.2%) cases had a deleterious mutation in BRCA1/2 compared with that of 28 (1.9%) in controls. After adjusting for age, the presence of a BRCA1 or BRCA2 mutation was significantly associated with the development of prostate cancer (odds ratio: 3.41). When results were stratified by gene, BRCA2 mutation carriers demonstrated an increased risk of prostate cancer (odds ratio: 4.78), whereas the risk in BRCA1 mutation carriers was not significantly increased (odds ratio: 2.20). In another Israeli study, 87 prostate cancer patients were compared with 87 healthy controls. The frequency distribution of Ashkenazi Jewish founder variant carriers was found to be the same in two groups. However, prostate cancer patients carrying BRCA1/2 mutations were found to have a much higher Gleason score (average above 8), than that for non-carrier prostate cancer patients (average 5.9) [44].

Thus, it was indicated that BRCA2 mutations may contribute more to prostate cancer risk whereas BRCA1/2 mutations may be related to the severity and the prognosis of the disease. This was confirmed by another Ashkenazi Jewish study. In a case-control study of 979 prostate cancer cases and 1,251 controls among men, the prostate cancer risk for BRCA2 mutation carriers was elevated (odd ratio=1.9), but not for BRCA1 mutation carriers compared to non-carriers. If stratified by Gleason score, BRCA2 founder mutation confers a 3-fold elevated risk (odd ratios = 3.2) of high-grade prostate cancer (Gleason score of 7 to 10). At the same time, the BRCA1- c.66_67delAG variant was observed to be associated with high Gleason score tumors [45].

However, no significant association of these Ashkenazi founder variants of BRCA1/2 genes with the prostate cancer risks was observed in other studies [44, 46-49]. Twenty-nine carriers of Ashkenazi Jewish founder BRCA1/2 mutations who developed prostate cancer were compared with non-carrier prostate cancer patients. No difference was seen in Gleason pattern, incidence of PIN or atypical adenomatous hyperplasia [50]. A meta-analysis on published research of six Ashkenazi-Jewish prostate cancer studies (3005 cases and 6834 controls) showed a non-statistically significant odds ratio 1.8 for the c.66_67delAG variant [51]. The inconsistent results observed in different studies may be due to the variations of sample size, mutation screening techniques, or patient selection criteria.

A five base-pair deletion, c.771_775delTCAAA (999del5) was detected in the Icelandic population and accounts for 40% of Icelandic male breast cancer patients [52]. In some of these affected families, multiple prostate cancer cases were also found. To evaluate the prostate cancer risk, a case control study shows that 2.7% of Icelandic prostate cancer patients below 65 years of age carry the c.771_775del5 mutation, compared with 0.5% in the healthy controls [53]. In breast cancer families carrying the c.771_775del5 variant, the relative risk of prostate cancer was 4.6 in male first-degree relatives [54]. This association was also confirmed by a large-scale family study from the Breast Cancer Linkage Consortium (BCLC) in Europe and North America. In this study of 173 breast or ovarian cancer families, 3047 individuals including 681 patients were enrolled. The relative risk for prostate cancer in male BRCA2 variant carriers was 4.65, and this risk increased to 7.33 in patients below 65 years of age [32]. These results suggest that BRCA2 mutation screening in men may help detect prostate cancer at an earlier clinical stage.

Additionally, the BRCA2 c.771_775del5 variant appears to be a marker for poor prognosis of prostate cancer in the Icelandic population [53], which was confirmed by a large-scale study [55]. In this study, 527 Icelandic prostate cancer patients with a family history of unselected breast cancer probands were enrolled. BRCA2 999del5 founder mutation carriers were detected in 30 of 527 (5.7%) patients. The prostate cancer-specific survival was evaluated by multivariable regression model with the adjustment for cancer stage and grade. Compared with non-carriers, BRCA2 c.771_775del5 carriers had a lower mean age at diagnosis (69.0 years versus 74.0 years), more advanced tumor stage (stages 3 or 4, 79.3% versus 38.6%), higher tumor grade (grades G3 - 4, 84.0% versus 52.7%), and shorter median survival time (2.1 years, versus 12.4 years). In addition, there was an increased risk of dying from prostate cancer (adjusting for year of diagnosis and birth, HR = 3.42), and the association remained after adjustment for stage and grade (HR = 2.35).

Poland has relative genetic homogeneity of its population. BRCA1 gene c.181T>G (300T>G, C61G), c.4035delA (4153delA) and c.5263-5264insC (5382insC) are three common founder variants in the Polish population. The frequency distribution of these three founder alleles in Polish breast cancer and breast-ovarian cancer patients was 34% (c.181T>G), 15.5% (c.4035delA) and 6% (c.5263-5264insC) [56]. The three allelic variants in total can account for 90% of all BRCA1 variants in the Polish population [56, 57].

To evaluate the prostate cancer risk, one case control study genotyped 1793 cases of prostate cancer and 4570 healthy controls in Poland. These results suggested that the presence of either c.181T>G or c.4035delA mutations was associated with an increased risk for prostate cancer (odds ratio=3.6) and the association was more significant for familial prostate cancer (odds ratio=12). The c.5263-5264insC variant is unlikely to contribute to prostate cancer risk in the Polish population [57]. Therefore, BRCA1 founder variants in the Polish population may be helpful to evaluate the prostate cancer risk of individuals in the affected families. These results may not be applied to other ethnic groups until specific studies in different populations are conducted.

In the Galician (Northwest Iberia) population, one splicing founder variant of c.211A>G (330A>G, R71G) is present in more than 50% of the breast and/or ovarian cancer families [58, 59]. This variant localized at position - 2 of exon 5 splice site in the BRCA1 gene, which changes the alternative transcript ratios, decreasing the full-length transcript (BRCA1-ex5FL) and increasing the transcript with a deletion of the last 22nt of exon 5 (BRCA1-Δ22ntex5) [60]. For prostate cancer risk, no significant contribution of this variant was found in a large-scale case control study [51]. In this study of 905 unselected prostate cancer patients and 936 healthy controls, four carriers of c.211A>G variants were found including one patient and three controls. No significant association of prostate cancer risk (odd ratios = 0.27) was observed with this variant. The low frequency distribution of variant carriers in patients (0.1%, 1 out of 905) and in controls (0.3%, 3 out of 936) might be one of the confounding factors. Thus a larger sample size may be needed to confirm the result.

BRCA1 mutation carriers were found to have an increased risk of prostate cancer in men. In a large-scale study of 913 prostate cancer patients in U.K., four deleterious BRCA1 germ-line mutations were detected, including c.66_67delAG (one of the founder variants in Ashkenazi Jews), c.212+1G>T (IVS5+1G>T), c.1954dupA (2080insA) and c.2475delC (2594delC). The estimated frequency of BRCA1 mutation carriers was 0.45% of the U.K. prostate cancer patients. These BRCA1 germ-line mutations confer a relative risk of ~3.75 fold for prostate cancer and an 8.6% cumulative risk by the age of 65 years [3]. In addition, the c.1954dupA mutation (truncated protein at codon 672) has been reported as a Pakistani founder mutation in breast and ovarian cancer patients [61]. The c.2475delC mutation (truncated protein at codon 845) appears to be a Scandinavian/Northern European founder mutation in breast and ovarian cancer patients [62, 63]. Further studies evaluating prostate cancer patients in Pakistani or Scandinavian/Northern European population, may be needed to further confirm the contribution of these variants to prostate cancer risk.

BRCA2 gene variants also contribute to the prostate cancer risk in the U.K. population. In a study of 1832 prostate cancer patients in the United Kingdom, BRCA2 gene variants were detected by a high-throughput multiplex fluorescence heteroduplex detection system. Nineteen protein-truncating mutations were detected. The prostate cancer risk of BRCA2 variant carriers was ~ 8.6-fold higher than non-carriers, corresponding to 15% of risk by age 65 [64]. These results suggest that in this relatively ethnically mixed population, the high-throughput screening of BRCA2 mutations may be needed to evaluate the contribution of this gene to prostate cancer risks.

BRCA1/2 mutations are associated with more aggressive prostate cancer. In a study of U.K. prostate cancer patients, the contribution of BRCA1 and BRCA2 mutation carriers to histopathology outcome was evaluated. In 20 prostate cancer patients carrying BRCA1/2 mutations, 15 BRCA2 mutations and 3 BRCA1 mutations were observed. Gleason scores of prostate cancer in the BRCA1/2 mutation carriers (8, 9 or 10) were significantly higher than those in the control group (P=0.012). It was indicated that the evaluation of BRCA1/2 mutation status may be a helpful prognostic factor for prostate cancer in the U.K. population. [65].

Three novel germ-line mutations in BRCA2 were found in a study of 38 non-Ashkenazi prostate cancer families [66], including 6710delACAA (c.6486_6489delACAA), 5531delTT, and 9078G>T (c.8850G>T, K2950N). In one prostate and breast cancer non-Ashkenazi family, a BRCA2 variant of 6051delA was also found [67]. In a Spanish family of breast, ovarian and prostate cancers, a BRCA2 germ-line variant of 5396delATTT was detected in a 45-year-old woman with bilateral breast cancer. This 4-nucleic acid deletion was also detected in her father with prostate cancer and her sister with breast cancer [68]. In a study of the Turkish population, 50 prostate cancer patients and 50 healthy controls were enrolled. One truncating mutation in BRCA2 c.4691A>T was detected in a high-risk prostate cancer patient diagnosed at 45 years of age [69].

BRCA2 germ-line mutations were found to contribute to the prostate cancer risk in a non-Ashkenazi (96% whites) study [30]. In this study, 263 men with diagnoses of early-onset prostate cancer (<=55 years of age) were enrolled. After screening of the complete coding sequence of BRCA2 for germ-line mutations, six protein-truncating mutations (2558insA, 6710del4, 7084del5, 7772insA, 8525delC, IVS17-1g>c) were found in six patients (2.3%), respectively. The relative risk of developing prostate cancer by age 56 years was 23-fold higher for germ-line BRCA2 mutation carriers compared with the non-carriers [30]. The same research group further investigated loss of heterozygosity (LOH) at BRCA2 in tumors of patients carrying BRCA2 mutations. LOH was found in 5 of the 6 tumors [70].

BRCA2 mutations are associated with the prostate cancer survival rates. In a study of non-Ashkenazi (~81% whites) prostate cancer patients, the survival rates were assessed in 21 patients carrying BRCA2 variants and 1844 non-carrier patients. Eighteen BRCA2 variants were detected. It was shown that median survival of the prostate cancer patients carrying BRCA2 variations was 4.8 years, which is much shorter than that of 8.5 years in non-carrier controls. Multivariate analysis confirmed that the poorer survival of prostate cancer in BRCA2 mutation carriers is associated with germ-line BRCA2 variants [70]. This result was confirmed by another prostate cancer study from 33 centers in 5 countries, which indicated that BRCA2 mutations are more likely to contribute to poor prostate cancer survival compared to BRCA1 mutations. In this study, the survival was compared between 182 patients carrying BRCA2 familial mutations and 119 patients carrying BRCA1 familial mutations. The median survival from diagnosis was 4.0 years for BRCA2 mutation carriers, compared with 8.0 years for BRCA1 mutation carriers [71]. In another study of 148 prostate cancer patients from 130 families in Australia and New Zealand, BRCA2 mutation carriers have an increased risk of death and prostate cancer-related death (hazard ratio=4.5), compared with non-carriers [72].

Several studies provide evidence that BRCA1 c.1067A>G (Gln356Arg) partially accounts for prostate cancer susceptibility and contributes to prostate cancer linkage to chromosome 17q21. The results from two small-scale family studies of Caucasians have been inconsistent. One study found only 1 of 22 prostate cancer families with the Arg356 variant [73] and the other study found all 14 prostate cancer families having the Arg356 variant [74]. In a large-scale study of 323 prostate cancer families, there is a significant association of this variant with prostate cancer susceptibility [75], and the prostate cancer linkage to the BRCA1 region on chromosome 17q21 was confirmed [76]. This result was also confirmed by studies in other populations. A case control study suggests that Arg356 allele carriers are more likely to develop prostate cancer than non-carriers in the African-American population [77]. Furthermore, the Arg356 allele distribution varies in different ethnic groups. The frequency of this variant is higher in Caucasians (prostate cancer patients 8% and healthy controls 6%) than that in African-Americans (5.5% and 1.5%) [75].

A large prospective international multicenter prostate cancer screening research study is called IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls; http://www.impact-study.co.uk ). The IMPACT study is the first prospective multicenter study of targeted prostate cancer screening in men with BRCA1 and BRCA2 mutations. A preliminary analysis of 300 individuals from the IMPACT study demonstrated that targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2 is associated with more aggressive prostate cancer. Results showed that the positive predictive value of PSA screening in BRCA1/2 mutation carriers is higher than that in non-carriers. Screening with BRCA1/2 mutations can detect clinically significant prostate cancer [34]. IMPACT plans to enroll 1700 subjects in the study, and the number is anticipated to complete enrollment by the end of 2012. All men enrolled will be screened for prostate cancer risk, progression and prognosis for at least 5 years. The IMPACT results will explore how BRCA1/2 mutations may contribute to prostate cancer management in the future.

Here we summarize the association studies of the BRCA1/2 sequence variants with prostate cancer in different ethnic groups. The absence of studies in other populations may limit the practical implications of these results to specific ethnic groups. Some studies summarized here are the familial prostate cancer studies or early-onset prostate cancer studies, which may not generalize to sporadic and/or late-onset prostate cancer cases. In addition, different mutation loci within the gene may produce differential effects on BRCA1 or BRCA2 function, thus the contribution of BRCA1/2 genes to prostate cancer may be mutation-specific. The contribution of BRCA1 mutations to prostate cancer is relatively weak, compared with much stronger evidence of the involvement of BRCA2 mutations in prostate cancer risk and prognosis. The most supportive studies of the link between BRCA1/2 mutations and prostate cancer come from populations with a high frequency of mutations, such as Ashkenazi Jews, Icelandic men, and the U.K. population. Prostate cancer is a polygenic disease, determined by multiple genes and the interaction between genetics and environment. It is important to integrate the information from the clinical manifestation, family history and genomic background for clinicians and patients to make a wise decision in medical counseling.

BRCA1 as a multifunctional tumor suppressor gene, likely plays multiple roles in different stages of prostate cancer pathophysiology. Overexpression of wild-type BRCA1 in a prostate cancer cell line was found to decrease the cell proliferation rate and increase sensitivity to chemotherapy drugs [78]. Furthermore, a naturally occurring BRCA1 splice variant BRCA1a (deletion of the major exon 11, amino acid 263-1365) was shown to significantly inhibit tumor mass in triple-negative prostate cancer xenografts [79]. In addition, more BRCA1 loss was found in lymph node metastasis (27%, 62 of 196) in prostate cancer patients than that in primary prostate cancer tumors (14%, 18 of 133), which might be due to the role of BRCA1 in the epithelial mesenchymal transition (EMT) [80].

On the other hand, BRCA1 can interact with multiple (even opposing) cellular signaling pathways in various cellular and animal models of prostate cancer. It was reported that BRCA1 was expressed at a high level in human prostate cancer compared to a very low level in normal prostate epithelium [81]. BRCA1-positive prostate tumors have much higher tumor proliferation index (47.0) than that of BRCA1-negative tumors (10.3) through regulating cell cycles to allow for DNA repair [23]. More patients carrying BRCA1-positive prostate tumors died of prostate cancer (26.7%, 16 of 60), compared with BRCA1-negative prostate tumors patients (7.2%, 24 out of 332) [23]. In transgenic tumor mouse models, Brca1 was overexpressed in aggressive prostate, breast, and lung cancers, in conjunction with a network of genes related to Brca1 function [82].

Compared to BRCA1, less basic science studies have been conducted on the BRCA2 gene. In one immuno-histochemistry study, BRCA2 protein was virtually absent in normal human prostate [19], whereas another study reported that nuclear BRCA2 protein is significantly reduced in premalignant PIN compared with normal prostate tissue. [83]. The different techniques used to detect BRCA2 expression under different physiological/pathological conditions may contribute to the inconsistent results. Different antibodies used in immunostaining might also influence the results of a particular study. In the animal model, it was proved that Brca2 can act as a tumor suppressor in prostate cancer tumorigenesis and there is a synergistic effect between Brca2 and the tumor suppressor Trp53. Brca2 conditional knock-outs in mouse prostate epithelia, develop focal hyperplasia and low-grade PIN over 12 months of age. Simultaneous deletion of Brca2 and Trp53 in prostate epithelia gave rise to focal hyperplasia and atypical cells at 6 months, leading to high-grade PIN in animals at 12 months of age [35]. Below we summarize the BRCA1 and BRCA2 regulators in the prostate cancer biology.

Prostate cancer and breast cancer are two hormone-related tumors. Estrogen receptor (ER)-α is thought to play a major role in breast cancer tumorigenesis [84]. BRCA1 suppresses estrogen-dependent transcriptional pathways in mammary epithelial cell proliferation, by binding with the estrogen-responsive enhancer element to block the transcriptional activation function (AF)-2 of ER-α [85]. Similarly, the androgen receptor (AR) signaling pathway plays an important role in prostate cancer tumorigenesis [86]. Transient transfection assays proved that BRCA1 physically interacts with the NH2-terminal activation function (AF)-1 of AR [87] and enhances AR -dependent transcriptional pathways, resulting in the increase of androgen-induced cell death in prostate cancer cells [88].

AR can play both stimulatory and inhibitory roles in prostate cancer cell proliferation and apoptosis, depending on the cofactor environment, somatic mutations and post-translational modifications of AR [87]. BRCA1 may serve as a signal 'directing' differential biological activities of AR towards the pathway of growth inhibition and apoptosis [89]. Furthermore, the role of BRCA1 may be regarded as a potentiation of AR transactivation in prostate cancer cells. It was reported that BRCA1-enhanced AR transactivation can act synergistically with AR-associated coregulators (ARAs), such as CBP, ARA55, and ARA70. AR transactivation can be increased from 5- to 90-fold by simultaneous addition of BRCA1 and ARAs [88].

BRCA1 can interact with the JAK-STAT signaling cascade in prostate cancer cells. BRCA1 physically interacts with JAK1 and JAK2, as shown by immunoprecipitation, leading to constitutive activation of STAT3, which promotes cell proliferation and suppresses apoptosis. This constitutive activation of STAT3 by BRCA1 provides a survival signal for escaping the tumor suppressing activity of BRCA1 and benefiting the growth of prostate cancer [90].

The insulin-like growth factor (IGF) system plays an important role in prostate cancer tumorigenesis. Clinical data suggests that men with higher serum levels of IGF-I and certain androgens are more likely to develop prostate cancer in the subsequent 6-9 years following assessment [91-94]. The insulin-like growth factor-I receptor (IGF-IR), mediating the effects of IGF-I and IGF-II on cell proliferation and differentiation, contributes to prostate cancer initiation and progression [92]. In addition, IGF-IR can interact with AR in prostate cancer tumorigenesis [92] and the alteration of the IGF signaling pathway may confer androgen independence in a human prostate cancer xenograft study [95].

BRCA1 can regulate IGF-IR activity in prostate cancer tumorgenesis, depending on AR status. Coexpression experiments in prostate cancer cells revealed that BRCA1 can differentially regulate IGF-IR gene in an AR-dependent manner [81]. In AR-negative prostate cancer cell lines, BRCA1 suppressed IGF-IR promoter activity (~50% reduction) and endogenous IGF-IR levels. In prostate cell lines expressing endogenous AR, BRCA1 enhanced the IGF-IR levels. The reduction of IGF-IR promoter activity by BRCA1 may be through physical interaction between BRCA1 and transcription factor Sp1, interfering the binding of Sp1 and cis-elements in the IGF-IR promoter [96]. On the other hand, the effect of BRCA1 on enhancing IGF-IR gene expression in prostate epithelial cells that express an active AR, is mediated through increasing AR transcription and subsequent AR-mediated IGF-IR expression [81]. That may be one of the reasons that BRCA1 reduction was observed more frequently in AR-negative prostate cancer.

On the other hand, it was shown that IGF-II, whose levels are largely increased in prostate carcinoma, is a potent stimulator of BRCA1 expression [91] [96]. An integrated network and cross-talk of hormone signaling pathway (such as AR and IGF) and regulators (such as BRCA1) should be considered as a whole to appreciate its complex role in prostate cancer biology.

The E3 ubiquitin ligase S-phase kinase-associated protein (Skp) 2, an oncogenic protein, is highly expressed in PIN and prostate cancer [97-99]. Skp2 was found to be an important regulator determining the abundance of BRCA2 in prostate cells, regulating BRCA2 protein levels through ubiquitin-mediated proteolysis [83, 100, 101]. In the prostate cancer cells, Skp2 regulation of BRCA2 expression behaves differently in the nucleus and the cytoplasm. In the studies of sporadic prostate cancer specimens, nuclear BRCA2 expression was significantly reduced, whereas cytoplasmic BRCA2 level was retained, although Skp2 expressed both in the nucleus and cytoplasm [83, 102]. Furthermore, the decrease of nuclear BRCA2 expression is more consistent in premalignant lesions than that in high-grade PIN, indicating that loss of BRCA2 by Skp2 more likely contributes to an early stage of prostate neoplastic transformation. Functional studies revealed that elevated Skp2 protein can down-regulate BRCA2 protein levels, resulting in increased migratory and proliferative capabilities in preneoplastic prostate cells. Thus, it was indicated that the BRCA2-Skp2 oncogenic pathway may serve as a target for the prevention of prostate cancer [83].

The abnormal interaction of cancer cells with extracellular matrix (ECM) and basement membrane (BM) proteins plays an important role during the cancer metastatic cascade, from carcinoma in situ to invasive carcinoma and metastasis [103-106]. It was reported that the adhesion of prostate cancer cells to the ECM protein collagen type I (COL1) can activate the COL1-β1 integrin signaling pathway, followed by activation of phosphatidylinositol (PI) 3-kinase/AKT, and upregulation of the Skp2 expression. Skp2 directly led to the degradation of BRCA2 and sustained BRCA2 depletion. Loss of BRCA2 can switch on cell proliferation and produce an abnormal proliferative response [100, 107]. Unlike cancer cells, in which adhesive stimuli activated PI 3-kinase/AKT signaling resulting in BRCA2 degradation and cancer cell proliferation and metastasis [100], in normal prostate cells, adhesive stimuli triggered the MAPK/ERK signaling pathway, resulting in upregulation of BRCA2 mRNA and protein.

Both PI 3-kinase/AKT signaling and MAPK/ERK signaling pathways are important to maintain BRCA2 homeostasis in prostate cells and altered BRCA2 levels may determine prostate cell fates. Defective MAPK/ERK signaling was found in prostate cancer cells and was associated with unresponsiveness to ECM adhesion, whereas PI 3-kinase/AKT signaling was triggered by adhesion stimuli leading to BRCA2 protein depletion and cell proliferation [108]. Reconstitution of MAPK/ERK effectively increased BRCA2 expression upon interaction with ECM proteins and reversed the neoplastic proliferation. Thus, restoring MAPK/ERK activity in prostate cells may be a candidate target for preventive interventions in prostate cancer tumorigenesis [108]. Furthermore, the inhibition of PI3-kinase/AKT and activation of the MAPK/ERK pathway leads to BRCA2 depletion, reduces BRCA2-mediated matrix metalloproteinase (MMP)-9 proteolysis and up-regulates MMP-9 protein levels, contributing to cancer cell migration and invasion [109]. Moreover, it was also shown that BRCA2 itself may inhibit the PI3-kinase/AKT signaling pathway and act as a regulatory element in an autocrine loop with PI3-kinase/AKT, which influences cancer cell proliferation and stromal invasion [109].

DNA-damaging agents such as adriamycin and camptothecin inhibit BRCA1/2 mRNA and protein expression in prostate cancer cell lines, which may serve as a cytoprotective effect in prostate cancer cells [110]. 1α, 25-dihydroxy (OH)2 vitamin D3 , a ligand for the vitamin D3 receptor (VDR) can induce BRCA1 mRNA/protein expression and its transcriptional activation in prostate cancer and breast cancer cell lines, and partly contributes to the anti-proliferative effects of 1α, 25(OH)2 D3 in prostate cancer and breast cancer tumorgenesis [111].

Phytochemicals indole-3-carbinol (I3C) and genistein are natural chemicals derived from cruciferous vegetables and soy, respectively, with potential cancer prevention activity for hormone-responsive breast and prostate cancers. Both I3C and genistein induce the expression of BRCA1/2 in prostate cancer and breast cancer cells in a time- and dose- dependent manner, through endoplasmic reticulum stress response signaling. BRCA1/2 may contribute to cancer prevention effects by I3C and genistein in breast and prostate cancer cells, partly due to modulating ER and/or AR activity [112].

BRCA1 and BRCA2 are multifunctional tumor suppressor genes, which can act pleiotropically in different stages of prostate cancer pathophysiology. The difficulties of detecting BRCA1/2 expression under various physiological/pathological conditions may limit the use of BRCA1/2 as a diagnostic or prognostic tool in the clinical practice. Multiple (even opposing) cellular signaling pathways are involved in BRCA1/2 related prostate cancer tumorigenesis, invasion and metastasis. BRCA2 homeostasis, maintained by the PI 3-kinase/AKT and MAPK/ERK signaling pathways, was found to be critical in determining cell fate during prostate cancer progression. Further understanding of the molecular pathways in prostate cancer may identify molecular markers that enhance cancer risk and prognostic evaluation of the disease, beyond prostate-specific antigen (PSA), Gleason score, and clinical stage. It also may help identify potential targets for new preventive or therapeutic interventions modifying the natural history of prostate cancer.

Prostate cancer is the most common non-cutaneous malignancy in men in developed countries. The majority of large-scale disease association studies indicate that BRCA1 and/or BRCA2 mutations contribute to clinical and/or pathological features of prostate cancer, such as an earlier diagnostic age, poorly-differentiated tumors and a relatively poor prognosis [44, 54, 67]. It will be important to replicate these studies in specific populations and evaluate clinical significance and economic benefit at the same time. Currently, clinicians and researchers recommend that males carrying BRCA1/2 mutations are screened for prostate cancer at an earlier age than the general population [32, 113]. On the other hand, translation of BRCA1/2 basic knowledge from the bench to the bedside is equally important to identify novel molecular targets for the prevention, diagnosis and therapy of prostate cancer.

Prostate cancer is a polygenic disease that can be influenced by various gene-gene interactions. A risk prediction model based on family history and multiple genetic variants has been applied to prostate cancer and has potential clinical utility [114]. The accuracy of the predictions in different independent populations and their potential role in prostate cancer screening needs to be further evaluated especially in prospective studies [114].

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