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The AKT/mamnialian target of rapamycin (AKT/mTOR) and ERK MAPK signaling pathways have been shown to cooperate in prostate cancer progression and the transition to androgen-independent disease. We have now tested the effects of combinatorial inhibition of these pathways on prostate tumorigenicity by performing preclinical studies using a genetically engineered mouse model of prostate cancer. We report here that combination therapy using rapamycin, an inhibitor of mTOR, and PD0325901, an inhibitor of MAPK kinase 1 (MEK; the kinase directly upstream of ERK), inhibited cell growth in cultured prostate cancer cell lines and tumor growth particularly for androgen-independent prostate tumors in the mouse model. We further showed that such inhibition leads to inhibition of proliferation and upregulated expression of the apoptotic regulator Bcl-2-interacting mediator of cell death (Bim). Furthermore, analyses of human prostate cancer tissue microarrays demonstrated that AKT/mTOR and ERK MAPK signaling pathways are often coordinately deregulated during prostate cancer progression in humans. We therefore propose that combination therapy targeting AKT/mTOR and ERK MAPK signaling pathways may be an effective treatment for patients with advanced prostate cancer, in particular those with hormone-refractory disease., Introduction Prostate cancer is one of the most common neoplasms, particularly among aging males in the United States. Like many adenocarcinomas, prostate tumors arise from preinvasive lesions, mainly prostatic intraepithelial [...]

Androgen independence is responsible for most prostate cancer lethality, yet currently there are no effective clinical treatments. We have been investigating the mechanisms underlying androgen-independent prostate cancer in Nkx3.1;Pten mutant mice, which display salient features of the disease, including a requirement for wild-type androgen receptor (AR) signaling. We now demonstrate that the Akt and Erk MAP kinase signaling pathways are activated in androgen-independent lesions of these mice. Forced activation of either Akt or Erk signaling in an androgen-responsive prostate cancer cell line promotes hormone-independent but AR-dependent growth in culture. Although these pathways act additively in culture, they act synergistically in vivo to promote tumorigenicity and androgen independence in the context of the prostate micro-environment. We propose that androgen independence emerges by means of epithelial--stromal competition, in which activation of Akt and Erk promotes AR activity in the prostate epithelium while counteracting antagonistic effects of the stroma. Akt signaling | androgen independence | MAP kinase signaling | mouse models of cancer

Changes in the substrate specificities of factors that irreversibly modify the histone components of chromatin are expected to have a profound effect on gene expression through epigenetics. Ezh2 is a histone-lysine methyltransferase with activity dependent on its association with other components of the Polycomb Repressive Complexes 2 and 3 (PRC2/3). Ezh2 levels are increasingly elevated during prostate cancer progression. Other PRC2/3 components also are elevated in cancer cells. Overexpression of Ezh2 in tissue culture promotes formation of a previously undescribed PRC complex, PRC4, that contains the [NAD.sup.+]-dependent histone deacetylase SirT1 and isoform 2 of the PRC component Eed. Eed2 is expressed in cancer and undifferentiated embryonic stem (ES) cells but is undetectable in normal and differentiated ES cells. The distinct PRCs exhibit differential histone substrate specificities. These findings suggest that formation of a transformation-specific PRC complex may have a major role in resetting patterns of gene expression by regulating chromatin structure. methylation | prostate cancer | Ezh2 | histone H1

In human prostate cancer, the frequent down-regulation of [p27.sup.kip1] protein expression is correlated with poor clinical outcome, yet [p27.sup.kip1] rarely undergoes mutational inactivation. Here, we investigate the consequences of reducing or eliminating [p27.sup.kip1] function for prostate carcinogenesis in the context of a mouse modeling lacking the Nkx3.1 homeobox gene and the Pten tumor suppressor. Unexpectedly, we find that triple mutant mice heterozygous for a [p27.sup.kip1] null allele ([Nkx3.1.sup.+/- or -/-]; [Pten.sup.+/-]; [p27.sup./-]) display enhanced prostate carcinogenesis, whereas mice that are homozygous null for [p27.sup.kip1] ([Nkx3.1.sup.+/- or -/-]; [Pten.sup.+/-]; [p27.sup.-/-]) show inhibition of cancer progression. Expression profiling reveals that Cyclin D1 is highly up-regulated in compound [p27.sup.kip1] heterozygotes, but is down-regulated in the compound [p27.sup.kip1] homozygous mutants. Using RNA interference in prostate cancer cell lines with distinct [p27.sup.kip1] gene doses, we show that prostate tumorigenicity depends on levels of [p27.sup.kip1] and that the consequences of [p27.sup.kip1] gene dosage can be attributed, in part, to altered levels of Cyclin D1. Our findings suggest that [p27.sup.kip1] possesses dosage-sensitive positive as well as negative modulatory roles in prostate cancer progression. Cyclin D1 | expression profiling | p27 | prostate cancer