Although mutations in the parkin gene are frequently associated with familial Parkinsonism, emerging evidence suggests that parkin also plays a role in cancers as a putative tumor suppressor. Supporting this, we show here that parkin expression is dramatically reduced in several breast cancer-derived cell lines as well as in primary breast cancer tissues. Importantly, we found that ectopic parkin expression in parkin-deficient breast cancer cells mitigates their proliferation rate both in vitro and in vivo, as well as reduces the capacity of these cells to migrate. Cell cycle analysis revealed the arrestment of a significant percentage of parkin-expressing breast cancer cells at the G1-phase. However, we did not observe significant changes in the levels of the G1-associated cyclin D1 and E. On the other hand, the level of cyclin-dependent kinase 6 (CDK6) is dramatically and selectively elevated in parkin-expressing breast cancer cells, the extent of which correlates well with the expression of parkin. Interestingly, a recent study demonstrated that CDK6 restrains the proliferation of breast cancer cells. Taken together, our results support a negative role for parkin in tumorigenesis and provide a potential mechanism by which parkin exerts its suppressing effects on breast cancer cell proliferation.Mutations in the parkin gene, located on chromosome 6q25.2-27, are a predominant cause of inherited parkinsonism (1). Accordingly, much of the interest in characterizing the function of the parkin gene has been directed toward understanding its role in neurodegeneration. However, aberrant parkin function has also been linked to several other disorders (2, 3), among which, to the development of several types of cancers (4). Comparatively, the role of parkin in these disorders is less well characterized.Supporting a role for parkin in cancers, a previous study by Cesari et al. (4) involving physical mapping combined with loss of heterozygosity (LOH) 4 analysis identified the 6q-located, 1.4 Mb parkin as a gene that is frequently targeted by hemizygous deletion and inactivation in both malignant tumors and tumorderived cell lines. Following this discovery, several other groups have reported parkin gene alterations and expression variability in a variety of tumor biopsies and tumor cell lines representing a wide range of cancers including breast and ovarian cancers (4 -8). Frequently, diminished or absent parkin expression was observed in these cancers, suggesting that parkin may have tumor suppression properties. Consistent with this, microcellmediated transfer of human chromosome 6 suppresses tumorigenicity in several cancer cell lines (9), and introduction of an intact chromosome 6 into MCF7 (a breast cancer cell line) restores its ability to senesce (10). Collectively, these studies support the existence of a tumor suppressor gene (TSG) on chromosome 6q and the potential candidacy of parkin as a TSG. However, whether and how the loss of parkin function contributes to the development of cancers are currently not well...

Mutations in the parkin gene, which encodes a ubiquitin ligase, are a major genetic cause of parkinsonism. Interestingly, parkin also plays a role in cancer as a putative tumor suppressor, and the gene is frequently targeted by deletion and inactivation in human malignant tumors. Here, we investigated a potential tumor suppressor role for parkin in gliomas. We found that parkin expression was dramatically reduced in glioma cells. Restoration of parkin expression promoted G 1 phase cell-cycle arrest and mitigated the proliferation rate of glioma cells in vitro and in vivo. Notably, parkin-expressing glioma cells showed a reduction in levels of cyclin D1, but not cyclin E, and a selective downregulation of Akt serine-473 phosphorylation and VEGF receptor levels. In accordance, cells derived from a parkin-null mouse model exhibited increased levels of cyclin D1, VEGF receptor, and Akt phosphorylation, and divided significantly faster when compared with wild-type cells, with suppression of these changes following parkin reintroduction. Clinically, analysis of parkin pathway activation was predictive for the survival outcome of patients with glioma. Taken together, our study provides mechanistic insight into the tumor suppressor function of parkin in brain tumors and suggests that measurement of parkin pathway activation may be used clinically as a prognostic tool in patients with brain tumor. Cancer Res; 72(10); 2543-53. Ó2012 AACR.