Aurora A Kinase Inhibition Leads to Senescence
Small molecules targeting Aurora A kinase have entered Phase I/II clinical trials. Here we show for the first time that inhibition of Aurora A kinase, using the small molecule inhibitor MLN8054, results in senescence both in vitro and in vivo. This example of chemotherapy-induced senescence adds to a growing list of chemotherapies shown to induce senescence in preclinical models. Senescence is just beginning to be understood as a common chemotherapy-induced cancer cell fate. With this awareness, it is likely that senescence will be used more frequently as a biomarker in the clinic.
Skp2 directs Myc suppression of p27Kip1 but is dispensable for lymphomagenesis
Myc suppression of the cell cycle inhibitor p27Kip1 involves the E3 ubiquitin ligase SCFSkp2. In the absence of either Skp2 or the small adaptor protein Cks1, SCFSkp2 is inactivated and p27Kip1 accumulates despite the presence of oncogenic Myc levels. In vivo, Skp2 deficiency has surprisingly modest effects on tumorigenesis in the Eμ-Myc lymphoma model, in contrast to previously shown delayed tumor onset in Cks1-deficient mice. These data genetically support clinical observation that show that high Skp2 levels are not always associated with decreased p27Kip1 expression. The results strongly support SCFSkp2-independent functions of Cks1 in tumor pathogenesis.
Regulation of β-Catenin by BRCA1
Both β-catenin and BRCA1 proteins are necessary for normal mammary gland development, whereas their aberrant activation was shown to be involved in carcinogenesis. We show a novel association between BRCA1 and β-catenin and that BRCA1 regulates the active form of β-catenin during oxidative stress responses. This form of β-catenin in the nucleus was absent or expressed at low levels in most BRCA1 familial breast tumors, compared with its expression in sporadic breast tumors and normal breast tissue. Thus, loss of BRCA1 leads to impaired expression of the nuclear form of β-catenin, which may contribute to the pathogenesis of breast cancer.
PAX5α in Mammary Carcinoma
Increased PAX5 expression has been reported for a variety of human malignancies, including metastatic breast cancer. However, the functional role of PAX5 in cancer remains unclear with conflicting reports of both tumor promoting and tumour suppressor functions. Vidal and colleagues investigated the role of one PAX5 isoform, PAX5α in breast cancer cell lines and observed that PAX5α significantly reduced cell oncogenicity, tumor growth, and enhanced epithelial cell characteristics. Thus, PAX5α promotes mesenchymal to epithelial transition, a process implicated in the establishment of distant metastases.
- ©2010 American Association for Cancer Research.