p18Ink4c and p53 Act as Tumor Suppressors in Cyclin D1―Driven Primitive Neuroectodermal Tumor

• Published in: Cancer research (Chicago, Ill.) Vol. 69; no. 2; pp. 440 - 448
• Main Authors: SAAB, Raya, RODRIGUEZ-GALINDO, Carlos, MATMATI, Kelly, REHG, Jerold E, BAUMER, Shannon H, KHOURY, Joseph D, BILLUPS, Catherine, NEALE, Geoffrey, HELTON, Kathleen J, SKAPEK, Stephen X
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.01.2009
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Cell Growth Processes - genetics; Child, Preschool; Cyclin D1 - biosynthesis; Cyclin D1 - genetics; Cyclin D1 - metabolism; Cyclin-Dependent Kinase Inhibitor p16 - metabolism; Cyclin-Dependent Kinase Inhibitor p18 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Disease Progression; Eye Proteins - genetics; Genes, bcl-1; Genes, p53; Humans; Hyperplasia; Infant; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neuroectodermal Tumors, Primitive - genetics; Neuroectodermal Tumors, Primitive - metabolism; Neuroectodermal Tumors, Primitive - pathology; Pharmacology. Drug treatments; Phosphorylation; Pineal Gland - metabolism; Pineal Gland - pathology; Retinoblastoma - genetics; Retinoblastoma Protein - genetics; Retinoblastoma Protein - metabolism; Retinol-Binding Proteins - genetics; Tumors; Primitive; TP53 Gene; C-Onc gene; Cyclin D1; Protooncogene; Tumor suppressor gene; Neuroectodermal tumor
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-08-1892

The retinoblastoma (RB) tumor suppressor pathway is likely important in primitive neuroectodermal tumors (PNET) of the brain. In fact, 10% to 15% of children born with RB mutations develop brain PNETs, commonly in the pineal gland. Cyclin D1, which in association with cyclin-dependent kinase (Cdk) 4 and Cdk6 phosphorylates and inactivates the RB protein, is expressed in 40% of sporadic medulloblastoma, a PNET of the cerebellum. To understand tumorigenic events cooperating with RB pathway disruption in brain PNET, we generated a transgenic mouse where cyclin D1 was expressed in pineal cells. Cyclin D1 enhanced pinealocyte proliferation, causing pineal gland enlargement. However, proliferation ceased beyond 2 weeks of age with reversal of Cdk4-mediated Rb phosphorylation despite continued expression of the transgene, and the pineal cells showed heterochromatin foci suggestive of a senescent-like state. In the absence of the p53 tumor suppressor, cell proliferation continued, resulting in pineal PNET that limited mouse survival to approximately 4 months. Interestingly, the Cdk inhibitor p18(Ink4c) was induced in the transgenic pineal glands independently of p53, and transgenic mice that lacked Ink4c developed invasive PNET, although at an older age than those lacking p53. Analogous to our mouse model, we found that children with heritable RB often had asymptomatic pineal gland enlargement that only rarely progressed to PNET. Our finding that the Cdk4 inhibitor p18(Ink4c) is a tumor suppressor in cyclin D1-driven PNET suggests that pharmacologic interventions to inhibit Cdk4 activity may be a useful chemoprevention or therapeutic strategy in cancer driven by primary RB pathway disruption.