Understanding the temporal sequence of genetic events that lead to prostate cancer progression and metastasis

Prostate cancer is the second most common cancer among men, with an estimated 903,000 newly diagnosed cases and 258,000 deaths per year worldwide (1). Although the prognosis is favorable in patients with localized disease, the 5-y survival rate drops to less than 30% for individuals with advanced, metastatic tumors (2). Although androgen deprivation therapy in the form of chemical or surgical castration is currently used to treat metastatic disease, response to treatment is usually temporary, and a significant percentage of patients invariably progress to castration-resistant prostate cancer (CRPC), which often arises due to micrometastases (3). The molecular mechanisms that contribute to tumor development, recurrence, and resistance to standard therapies are poorly understood, making it extremely difficult to predict which patients with treatable, early-stage prostate cancer will progress to lethal forms of the disease. Fortunately, global and computational analyses of the prostate cancer genome have provided us with part of the foundation needed to tackle this issue. One of the first genomewide studies was published in 2005 (4) and showed that ∼50% of all prostate tumors contain chromosomal rearrangements that involve the ETS family of transcription factors, primarily in the formof theTMPRSS2ERG translocation, which fuse the ETS family member ERG with the androgen-regulated TMPRSS2 gene. This and other translocations involving ETS family genes are present even at early stages of the disease and are specific to prostate cancer (4). However, as the disease progresses and androgen receptor (AR) dependence is lost, these genetic lesions cooperate with signaling pathways, such those mediated by pRB, RAS/RAF, and phosphatidylinositol 3-kinase (PI3K)/PTEN/AKT, which are altered in a more “global” sense to promote metastasis (5). In PNAS, Aytes et al. (6) describe the temporal progression and the consequence of molecular activation of the PI3K and RAS signaling pathways during prostate cancer metastasis. Using a unique genetically engineered mouse model of prostate cancer that allows lineage tracing, the authors demonstrate that the spread of tumor cells is an early event that actually occurs well before the onset of metastasis. They further show that metastasis is temporally coincident with the expression of ETV4, a member of the PEA3 subfamily of ETS transcription factors that mediates late events associated with metastasis (Fig. 1). Prior studies have demonstrated that the PI3K and RAS pathways are altered in ∼40% of primary prostate tumors, yet this number jumps to more than 90% in cases of metastatic disease (5). Both pathways often cooperate in the control of numerous cellular processes, including proliferation, survival, and metabolism of normal cells. In prostate cancer, PI3K activation is largely mediated by loss of function of the PTEN phosphatase, although there are anomalies seen in either the regulation or expression levels of other proteins that are part of this pathway (3). Loss of PTEN in mouse models results in the development of precancerous lesions in the prostate and, when combined with other mutations, leads to invasive carcinomas (7–9). Furthermore, PI3K activation correlates with decreased AR-mediated signaling, suggesting a key role for this pathway in castrationresistant tumors (8). Accordingly, in humans, prostate cancer in the absence of PTEN is associated with recurrence, shortened times to metastasis, resistance to therapy, and an overall poorer prognosis (3). This is likely due to the fact that androgen-resistant growth, as shown in mouse models, is inherent to PTEN-null prostate tumor cells, regardless of tumor stage (7). Despite the fact that RAS/RAF signaling is also activated in prostate cancer, far less is known about its involvement in disease initiation and progression. Compared with PTEN levels that are highest in benign prostatic hyperplasia and untreated prostate cancers, phospho-MAPK (pMAPK), which reflects activation of the RAS pathway, increases significantly in neoadjuvant-treated, recurrent, and CRPC patients. Interestingly, pMAPK levels are also comparatively elevated in metastatic bone lesions, which is in stark contrast to that of PTEN (10). These data indicate that both pathways are activated and cooperate primarily during late stage disease development, as predicted by analysis of copy number alterations in prostate cancer genomes (5, 10). The requirement for multiple cooperating events is supported by the use of mouse models that show that activation of Kras (G12D) alone in the prostatic epithelium is insufficient to promote the development of prostate cancer. This observation in mice is similar to that previously shown for the TMPRSS2-ERG fusion, whichwas onlyweakly oncogenic when expressed as a transgene in the prostate (11). However, expression of Normal Prostate Prosta c Intraepithelial Neoplasia (PIN) Invasive Prostate Carcinoma