The G1 phase Cdks regulate the centrosome cycle and mediate oncogene-dependent centrosome amplification

It has well been established that centrosome amplification is a distinct feature of most cancer cells. With this observation came the hypothesis that this phenotype can drive genomic instability and subsequent tumorigenesis. Abnormal centrosome biology, including centrosome amplification and structural abnormalities frequently occurs in most types of solid tumors, as well some leukemias and lymphomas. Specifically, those cancer types include testicular germ cell, liposarcoma, adrenocortical, bronchial, bladder, cerebral primitive neuroectodermal, cervical, prostate, breast, squamous cell carcinomas of the head and neck, myeloma, and T-cell leukemia [1-13]. Work done in haematopoietic malignancies demonstrates that centrosome amplification in myelomas correlates with a specific gene expression signature, and can serve as a prognostic factor in patients [14].One of the tumor types in which the relationship between centrosome amplification and cancer is better understood are breast cancers. The vast majority (80-100%) of breast tumors display centrosome amplification [15]. Breast adenocarcinoma cells have a much higher frequency of centrosome defects, including amplification of number [15,16], increased volume and supernumerary centrioles, when compared to normal breast tissue [16]. Similar phenotypes can also be found in pre-invasive in situ ductal carcinoma, and in pre-malignant breast lesions, suggesting that these aberrations occur early in breast carcinogenesis [4,15,17]. In support of this data, molecular analyses have found that the centrosome pathway is highly enriched for SNPs that are associated with breast cancer risk [18]. In addition to being involved in initiation, having extensive areas of centrosome amplification in breast tumors correlates with axillary lymph node involvement, suggesting that centrosome amplification also contributes to the most malignant characteristics of breast cancer cells [19]. Various rodent models have also given support to the