Androgen receptor signaling and mutations in prostate cancer

Normal and neoplastic growth of the prostate gland are dependent on androgen receptor （AR） expression and function. Androgenic activation of the AR, in association with its coregulatory factors, is the classical pathway that leads to transcriptional activity of AR target genes. Alternatively, cytoplasmic signaling crosstalk of AR by growth factors, neurotrophic peptides, cytokines or nonandrogenic hormones may have important roles in prostate carcinogenesis and in metastatic or androgen-independent （AI） progression of the disease. In addition, cross-modulation by various nuclear transcription factors acting through basal transcriptional machinery could positively or negatively affect the AR or AR target genes expression and activity. Androgen ablation leads to an initial favorable response in a significant number of patients; however, almost invariably patients relapse with an aggressive form of the disease known as castration-resistant or hormone-refractory prostate cancer （PCa）. Understanding critical molecular events that lead PCa cells to resist androgen-deprivation therapy is essential in developing successful treatments for hormone-refractory disease. In a significant number of hormone-refractory patients, the AR is overexpressed, mutated or genomically amplified. These genetic alterations maintain an active presence for a highly sensitive AR, which is responsive to androgens, antiandrogens or nonandrogenic hormones and collectively confer a selective growth advantage to PCa cells. This review provides a brief synopsis of the AR structure, AR coregulators, posttranslational modifications of AR, duality of AR function in prostate epithelial and stromal cells, AR-dependent signaling, genetic changes in the form of somatic and germline mutations and their known functional significance in PCa cells and tissues.

Saposin C stimulates growth and invasion,activates p42/44 and SAPK/JNK signaling pathways of MAPK and upregulates uPA/uPAR expression in prostate cancer and stromal cells

Aim:To determine the effect of saposin C (a known trophic domain of prosaposin) on proliferation,migration and invasion,as well as its effect on the expression of urokinase plasmonogen activator (uPA),its receptor (uPAR) and matrix metalloproteinases (MMP)-2 and -9 in normal and malignant prostate cells.In addition,we tested whether saposin C can activate p42/44 and stress-activated protein kinase/c-Jun NH_2-terminal kinase (SAPK/JNK) signal transduction pathways of the mitogen-activated protein kinase (MAPK) superfamily.Methods:We employed West- ern blot analysis,phospho-specific antibodies,cell proliferation assay,reverse transcriptase-polymerase chain reaction, in vitro kinase assays and migration and invasion to determine the effect of saposin C on various biological behaviors of prostate stromal and cancer cells.Results:Saposin C,in a cell type-specific manner,upregulates uPA/uPAR and immediate early gene c-Jun expression,stimulates cell proliferation,migration and invasion and activates p42/44 and SAPK/JNK MAPK pathways in prostate stromal and cancer cells.Normal prostate epithelial cells were not responsive to saposin C treatment in the above studies.Conclusion:Saposin C functions as a multipotential modulator of diverse biological activities in prostate cancer and stromal cells.These results strongly suggest that saposin C functions as a potent growth factor for prostatic cells and may contribute to prostate carcinogenesis and/or the development of hormone-refractory prostate cancer.

Identification of a novel germline missense mutation of the androgen receptor in African American men with familial prostate cancer

Race, family history and age are the unequivocally accepted risk factors for prostate cancer （PCa）. Androgen receptor （AR）-dependent signaling is an important element in prostate carcinogenesis and its progression to metastatic disease. We examined the possibility of genomic changes in the AR in association with familial PCa in African Americans who have a higher incidence and mortality rate and a clinically more aggressive disease presentation than Caucasians. Genomic DNAs of 60 patients from 30 high-risk African American and Caucasian families participating in the Louisiana State University Health Sciences Center genetic linkage study of PCa were studied. Exon-specific polymerase-chain reaction, bi-directional automated sequencing and restriction enzyme genotyping were used to analyze for mutations in the coding region of the AR gene. We identified a germline AR （A1675T） （T559S） substitution mutation in the DNA-binding domain in three PCa-affected members of an African- American family with a history of early-onset disease. The present study describes the first AR germline mutation in an African-American family with a history of familial PCa. The AR （T559S） mutation may contribute to the disease by altering AR DNA-binding affinity and/or its response to androgens, non-androgenic steroids or anti-androgens. Additional studies will be required to define the frequency and contribution of the AR （A 1675T） allele to early-onset and/or familial PCa in African Americans.

Glutamate, a metabolic biomarker of aggressiveness and a potential therapeutic target for prostate cancer

Glutamate is extensively involved in metabolic and oncogenic pathways. Univariate and multivariate analyses showed that serum glutamate levels directly correlated with Gleason score （≤ 6 vs.≥ 8） and primary prostate cancer （PCa） aggressiveness. Compared with Caucasian Americans, serum glutamate levels were higher in African Americans with metastatic castrate- resistant PCa than in the patients with primary tumors.

DNA methylome and the complexity, of discovering prostate cancer biomarkers

Prostate cancer （PCa） remains the most common malignancy and a leading cause of cancer-related ＇deaths in men. Molecular discrimination at an early stage between indolent and aggressive primary tumors in pathologically confirmed PCa is required to develop personalized therapeutic interventions.

Comment on ＂Effect of transferred NK4 gene on proliferation, migration, invasion, and apoptosis of human prostate cancer DU145 cells＂ by Dan Yue et al. in Asian Journal of Androtogy

Hepatocyte growth factor/scatter factor （HGF/SF） interacting with its cell surface receptor tyrosine kinase （RTK） c-met proto-oncogene drives downstream signaling pathways which lead to cell proliferation, migration, invasion, apoptotic cell-death protection, angiogenesis during embryogenesis, repair and regeneration, and neoplastic growth and metastatic progression [1-6].

Commentary on＂Region 2 of 8q24 is associated with the risk of aggressive prostate cancer in Caribbean men of African descent from Guadeloupe （French West Indies）＂

Men of African ancestry in particular have a high incidence, mortality, and worst prognosis for prostate cancer （PCa） among other racial and ethnic populations. Environmental and genetic factors have been accounted at least partially as the underlying reasons for such disproportionate ethnic differences. Identification of inheritable genetic factors to predict PCa risk and aggressiveness in African men can assist epidemiologists, geneticists, and clinicians to target them for prevention, screening, and efficient treatment.