How breast cancers are able to disseminate and metastasize is poorly understood. Using a hyperplasia transplant system, we show that tumor dissemination and metastasis occur in discrete steps during tumor progression. Bioinformatic analysis revealed that loss of the transcription factor GATA-3 marked progression from adenoma to early carcinoma and onset of tumor dissemination. Restoration of GATA-3 in late carcinomas induced tumor differentiation and suppressed tumor dissemination. Targeted deletion of GATA-3 in early tumors led to apoptosis of differentiated cells, indicating that its loss is not sufficient for malignant conversion. Rather, malignant progression occurred with an expanding GATA-3-negative tumor cell population. These data indicate that GATA-3 regulates tumor differentiation and suppresses tumor dissemination in breast cancer.

A B S T R A C T PurposeOlder men are more likely to be diagnosed with high-risk prostate cancer and to have lower overall survival. As a result, age often plays a role in treatment choice. However, the relationships among age, disease risk, and prostate cancer-specific survival have not been well established. Patients and MethodsWe studied men in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) database with complete risk, treatment, and follow-up information. High-risk patients were identified by using the validated Cancer of the Prostate Risk Assessment (CAPRA) score. Competing risks regression was used to identify the independent impact of age on cancer-specific survival. We also analyzed the effect of local treatment on survival among older men with high-risk disease. ResultsIn all, 26% of men age Ն 75 years presented with high-risk disease (CAPRA score 6 to 10). Treatment varied markedly with age across risk strata; older men were more likely to receive androgen deprivation monotherapy. Controlling for treatment modality alone, or for treatment and risk, age did not independently predict cancer-specific survival. Furthermore, controlling for age, comorbidity, and risk, older men with high-risk tumors receiving local therapy had a 46% reduction in mortality compared with those treated conservatively. ConclusionOlder patients are more likely to have high-risk prostate cancer at diagnosis and less likely to receive local therapy. Indeed, underuse of potentially curative local therapy among older men with high-risk disease may in part explain observed differences in cancer-specific survival across age strata. These findings support making decisions regarding treatment on the basis of disease risk and life expectancy rather than on chronologic age.

Type IIA DNA topoisomerases play multiple essential roles in the management of higher-order DNA structure, including modulation of topological state, chromosome segregation, and chromatin condensation. These diverse physiologic functions are all accomplished through a common molecular mechanism, wherein the protein catalyzes transient cleavage of a DNA duplex (the G-segment) to yield a double-stranded gap through which another duplex (the T-segment) is passed. The overall process is orchestrated by the opening and closing of molecular "gates" in the topoisomerase structure, which is regulated by ATP binding, hydrolysis, and release of ADP and inorganic phosphate. Here we present two crystal structures of the ATPase domain of human DNA topoisomerase II␣ in different nucleotide-bound states. Comparison of these structures revealed rigid-body movement of the structural modules within the ATPase domain, suggestive of the motions of a molecular gate.Type IIA DNA topoisomerases (Topo IIs) 4 are complex multifunctional enzymes that use the energy of ATP hydrolysis to resolve topological problems encountered in the genome during cell growth and division (reviewed in Refs. 1-3). The functions served by Topo II enzymes are essential for cell viability; hence these evolutionarily conserved enzymes have been widely exploited as targets for clinically important antibiotics and anti-tumor drugs (4). A broad range of biochemical and structural studies has provided a detailed understanding of the molecular mechanism employed by Topo II enzymes, including those of eukaryotic origin (1-3). Eukaryotic Topo II is a homodimer having two functionally distinct domains per subunit, an N-terminal ATPase domain, and a C-terminal DNA cleavage-religation domain. Structures of these individual functional domains from Saccharomyces cerevisiae have been solved (5-7), leading to a composite picture of Topo II as a theta-shaped dimer having three major dimer interfaces, one at the N terminus, one in the middle, and one at the C terminus. Each of the three interfaces constitutes a gate allowing capture and restricting passage of duplex DNA. In the absence of DNA and ATP, the N-terminal gate (N-gate) is open, and the middle (M-gate) and C-terminal (C-gate) gates are closed. According to the two-gate model (8), the Topo II catalytic cycle is initiated by the binding of the G-segment to the middle gate. Binding of ATP then triggers the closing of the N-gate via establishment of a dimer interface in the ATPase domain and captures the T-segment when present. Closing of the N-gate promotes the cleavage of the G segment and opening of the M-gate. The T segment then passes through the M-gate, after which the M-gate closes and the C-gate opens to allow release of the passed T-segment. Finally, the C-gate closes, and the N-gate opens to prepare for another round of strand passage (9). Following multiple rounds of T-segment passage, the G-segment is released from Topo II.One of the central mysteries surrounding Topo II structure and function concerns the m...

The GATA family of transcription factors plays essential roles in the specification and maintenance of differentiated cell types. GATA-3 was identified in a microarray screen of the mouse mammary gland as the most highly expressed transcription factor in the mammary epithelium and is expressed exclusively in the luminal epithelial cell population. Targeted deletion of GATA-3 in mammary glands leads to profound defects in mammary development and inability to specify and maintain the luminal cell fate in the adult mouse. In breast cancer, GATA-3 has emerged as a strong predictor of tumor differentiation, estrogen-receptor status, and clinical outcome. GATA-3 maintains tumor differentiation and suppresses tumor dissemination in a mouse model of breast cancer. This review explores our current understanding of GATA-3 signaling in luminal cell differentiation, both in mammary development and breast cancer.