Overexpression of the HER2͞Neu protooncogene has been linked to the progression of breast cancer. Here we demonstrate that the growth of prostate cancer LNCaP cells can also be increased by the stable transfection of HER2͞Neu. Using AG879, a HER2͞Neu inhibitor, and PD98059, a MAP kinase inhibitor, as well as MAP kinase phosphatase-1 (MPK-1), in the transfection assay, we found that HER2͞Neu could induce prostate-specific antigen (PSA), a marker for the progression of prostate cancer, through the MAP kinase pathway at a low androgen level. Reporter assays and mammalian two-hybrid assays further suggest this HER2͞Neu-induced androgen receptor (AR) transactivation may function through the promotion of interaction between AR and AR coactivators, such as ARA70. Furthermore, we found this HER2͞Neu 3 MAP kinase 3 AR-ARAs 3 PSA pathway could not be blocked completely by hydroxyf lutamide, an antiandrogen used in the treatment of prostate cancer. Together, these data provide a novel pathway from HER2͞Neu to AR transactivation, and they may represent one of the reasons for the PSA re-elevation and hormone resistance during androgen ablation therapy in prostate cancer patients.

Neuroendocrine (NE) cells represent a minor cell population in the epithelial compartment of normal prostate glands and may play a role in regulating the growth and differentiation of normal prostate epithelia. In prostate tumor lesions, the population of NE-like cells, i.e., cells exhibiting NE phenotypes and expressing NE markers, is increased that correlates with tumor progression, poor prognosis, and the androgen-independent state. However, the origin of those NE-like cells in prostate cancer (PCa) lesions and the underlying molecular mechanism of enrichment remain an enigma. In this review, we focus on discussing the distinction between NE-like PCa and normal NE cells, the potential origin of NE-like PCa cells, and in vitro and in vivo studies related to the molecular mechanism of NE transdifferentiation of PCa cells. The data together suggest that PCa cells undergo a transdifferentiation process to become NE-like cells, which acquire the NE phenotype and express NE markers. Thus, we propose that those NE-like cells in PCa lesions were originated from cancerous epithelial cells, but not from normal NE cells, and should be defined as 'NE-like PCa cells'. We further describe the biochemical properties of newly established, stable NE-like lymph node carcinoma of the prostate (LNCaP) cell lines, transdifferentiated from androgen-sensitive LNCaP cells under androgen-deprived conditions. Knowledge of understanding NE-like PCa cells will help us to explore new therapeutic strategies for treating PCa.

The proliferation and differentiation of normal prostate epithelial cells depends upon the action of androgens produced by the testis. Prostate cancers retain the ability to respond to androgens in the initial stages of cancer development, but progressively become independent of exogenous androgens in advanced stages of the disease while maintaining the expression of functional androgen receptor (AR). In the present study, we have determined the potential of prostate cancer cells to synthesize androgens from cholesterol which may be involved in intracrine regulation of AR in advanced stages of the disease‥ Established androgen-independent prostate cancer cell lines, PC3 and DU145 cells, expressed mRNA and proteins for scavenger receptor type B1 (SRB1), steroidogenic acute regulatory (StAR) protein, cytochrome P450 cholesterol side chain cleavage (P450scc), 3β-hydroxysteroid dehydrogenase (3β-HSD) and other enzymes involved in androgen biosynthesis. Expression of all these proteins and enzymes was significantly higher in the androgen-independent derivative of LNCaP prostate cancer cells (C81) than in the androgen-dependent cell line (C33). In serum-free cultures, the androgen-independent C81 cells secreted ~5 fold higher testosterone than C33 cells as determined in the conditioned media by immunoassays. These cells could also directly convert radioactive cholesterol into testosterone which was identified by thin layer chromatography. These results for the first time show that prostate cancer cells in advanced stages of the disease could synthesize androgens from cholesterol and hence are not dependent upon testicular and/or adrenal androgens.

Androgen plays a critical role in regulating the growth and differentiation of normal prostate epithelia, as well as the initial growth of prostate cancer cells. Nevertheless, prostate carcinomas eventually become androgen-unresponsive, and the cancer is refractory to hormonal therapy. To gain insight into the mechanism involved in this hormone-refractory phenomenon, we have examined the potential role of the androgen receptor (AR) in that process. We have investigated the expression of AR and two prostate-specific androgen-responsive antigens, prostatic acid phosphatase (