For metastasis to occur, tumor cells must first detach from their tissue of origin. This requires altering both the tissue of origin and the cancer cell. Once detached, cancer cells in circulation must also acquire survival mechanisms. Although many may successfully disseminate, variation exists in the efficiency with which circulating tumor cells home to and invade the bone marrow as metastastic seeds. Disseminated tumor cells that do successfully invade the marrow are secured by cell–cell and cell–extracellular matrix adhesion. However, establishing a foothold in the marrow is not sufficient for disseminated tumor cells to create metastases. A significant latent phase must be overcome by either rescuing cellular proliferation or attenuating micrometastatic mass dormancy programs. Finally, growing metastases fuel osteolysis, osteoblastogenesis and T-cell differentiation, creating a variety of tumor phenotypes. Each step in the metastatic cascade is rich in biological targets and mechanistic pathways.

Prostate cancers display a range of clinical behavior, from slow-growing tumors of minor clinical significance to locally aggressive and ultimately metastatic disease. Human prostate adenocarcinoma has a mature luminal phenotype characterized by cytokeratin 8 (CK8) and androgen receptor (AR) expression and prostate-specific antigen (PSA) production. Progressive prostate cancer is almost always treated with androgen deprivation therapy; however, despite such treatment, approximately 10% of prostate cancers progress to metastatic disease.1 Defining mechanisms of resistance to androgen deprivation and progression to metastasis would be significantly aided by the availability of genetically defined models of prostate cancer progression.One of the most common genetic alterations in prostate cancer is deletion of at least one copy of the PTEN tumor suppressor, which occurs in approximately 70% of human prostate cancers. Biallelic deletion of PTEN and the associated increase in AKT phosphorylation, which occurs in roughly 25% of prostate cancers, is correlated with resistance to androgen deprivation therapy.2 A recent genomic profiling study of mostly primary prostate cancers demonstrated that 24% of cases had either a heterozygous or homozygous copy number loss of TP53.3 Other large-scale studies using combined immunohistochemistry (IHC) and sequencing approaches have shown that TP53 mutations occur in approximately 5% of primary tumors and at much higher frequencies in lymph node metastases (16%) and castrate-resistant (26%) tumors. 4,5 In addition, TP53 mutations were found to be independent predictors of tumor recurrence in low-and intermediate-grade cancers. Thus, loss of PTEN and aberrations of TP53 are implicated in aggressive forms of human prostate cancer.

Transcriptional repressors and corepressors play a critical role in cellular homeostasis and are frequently altered in cancer. C-terminal binding protein 1 (CtBP1), a transcriptional corepressor that regulates the expression of tumor suppressors and genes involved in cell death, is known to play a role in multiple cancers. In this study, we observed the overexpression and mislocalization of CtBP1 in metastatic prostate cancer and demonstrated the functional significance of CtBP1 in prostate cancer progression. Transient and stable knockdown of CtBP1 in prostate cancer cells inhibited their proliferation and invasion. Expression profiling studies of prostate cancer cell lines revealed that multiple tumor suppressor genes are repressed by CtBP1. Furthermore, our studies indicate a role for CtBP1 in conferring radiation resistance to prostate cancer cell lines. In vivo studies using chicken chorioallantoic membrane assay, xenograft studies, and murine metastasis models suggested a role for CtBP1 in prostate tumor growth and metastasis. Taken together, our studies demonstrated that dysregulated expression of CtBP1 plays an important role in prostate cancer progression and may serve as a viable therapeutic target.