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High Gleason grade prostate carcinomas are aggressive, poorly differentiated tumors that exhibit diminished estrogen receptor beta (ERbeta) expression. We report that a key function of ERbeta and its specific ligand 5alpha-androstane-3beta,17beta-diol (3beta-adiol) is to maintain an epithelial phenotype and repress mesenchymal characteristics in prostate carcinoma. Stimuli (TGF-beta and hypoxia) that induce an epithelial-mesenchymal transition (EMT) diminish ERbeta expression, and loss of ERbeta is sufficient to promote an EMT. The mechanism involves ERbeta-mediated destabilization of HIF-1alpha and transcriptional repression of VEGF-A. The VEGF-A receptor neuropilin-1 drives the EMT by promoting Snail1 nuclear localization. Importantly, this mechanism is manifested in high Gleason grade cancers, which exhibit significantly more HIF-1alpha and VEGF expression, and Snail1 nuclear localization compared to low Gleason grade cancers.

Inhibitor-of-Apoptosis (IAP) proteins contribute to tumor progression, but the requirements of this pathway are not understood. Here, we show that intermolecular cooperation between XIAP and survivin stimulates tumor cell invasion and promotes metastasis. This pathway is independent of IAP inhibition of cell death. Instead, a survivin-XIAP complex activates NF-kappaB, which in turn leads to increased fibronectin gene expression, signaling by beta1 integrins, and activation of cell motility kinases FAK and Src. Therefore, IAPs are direct metastasis genes, and their antagonists could provide antimetastatic therapies in patients with cancer.

Although the genesis of invasive squamous cell carcinoma (SCC) from stratified epithelia of the skin is considered to be a complex, multistage process, recent work on human epidermis reveals that sustained Ras signaling coupled with suppression of Ras-induced growth arrest is sufficient to drive the entire process and that the alpha6beta4 integrin and its laminin 5 ligand are essential components of this process.

Although the genesis of invasive squamous cell carcinoma (SCC) from stratified epithelia of the skin is considered to be a complex, multistage process, recent work on human epidermis reveals that sustained Ras signaling coupled with suppression of Ras-induced growth arrest is sufficient to drive the entire process and that the α6β4 integrin and its laminin 5 ligand are essential components of this process.