Cyclin D1 and retinoblastoma susceptibility gene alterations in non‐small cell lung cancer

Abstract

Among the major regulators of the G 1 restriction point are cyclin D1 and the retinoblastoma gene product (RB). In non-small cell lung cancer (NSCLC), the cyclin D1 gene is amplified/over-expressed in almost 50% of cases, and RB is inactivated in 6-32% of cases. It is of interest to evaluate concurrently the alterations of both genes on the same series of NSCLCs, to investigate whether cyclin D1 and RB alterations are alternative pathways leading to inactivation of the G 1 restriction point or if they can occur in the same tumor, possibly exerting an additive effect on cancer progression. We investigated a series of 57 NSCLCs, analyzing cyclin D1 and RB at the gene and protein levels by Southern blot, Northern blot and immunohistochemistry. The cyclin D1 gene was amplified in 18 cases. cyclin D1 immunoreactivity was seen in 25 tumors. Amplification and expression were significantly associated. RB immunohistochemical expression was absent in 9 of 42 informative cases. RB mRNA expression was low to absent in 9 of 45 informative cases. cyclin D1 amplification was associated with normal RB mRNA, and cyclin D1 over-expression was associated with normal RB immunoreactivity, supporting the hypothesis that alterations of cyclin D1 and RB are alternative mechanisms by which tumor cells may escape the G 1 restriction point. A concurrent alteration of RB and cyclin D1 was seen in a small subset of NSCLCs. Abnormalities of cyclin D1 and/or RB at the gene and/or expression level were present in more than 90% of cases, stressing that cyclin D1 and/or RB alterations represent an important step in lung tumorigenesis. Int. J. Cancer 75:187-192, 1998. Wiley-Liss, Inc.The control of mammalian cell proliferation occurs largely during the G 1 phase of the cell cycle (Pardee, 1989). This control mechanism, known as the restriction point or R-point, consists of a multimolecular system composed of cyclins D, cyclin-dependent kinases (cdk), cdk inhibitors and the retinoblastoma protein (RB) . Alterations of this pathway may represent an obligatory step in tumorigenesis; it is important to evaluate the abnormalities of not only the single genes involved in the pathway, but also the functional alterations of the whole multicomponent mechanism Lukas et al., 1995).Among the major regulators of the G 1 restriction point are cyclin D1 and RB. cyclin D1, by complexing with the cyclin-dependent kinases cdk4 and cdk6, promotes cell proliferation by phosphorylating RB and inactivating its growth-restraining properties (Hatekayama et al., 1994). The interplay of cyclin D1, cdk and cdk inhibitors operates upstream to the RB, and most data support the hypothesis that both the G 1 -accelerating function of cyclin D1/cdk and the growth suppression by cdk inhibitors strictly require the presence of a functional RB . The cyclin D1 gene is amplified/rearranged and/or over-expressed in several types of human neoplasms (Bartkova et al., 1995), and the RB gene is the archetypal tumor suppressor that is inactivated by mutations, deletions or sequestrations of...

Development of pulmonary bronchiolo-alveolar adenocarcinomas in transgenic mice overexpressing murine c- myc and epidermal growth factor in alveolar type II pneumocytes

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Role of cell cycle regulators in lung carcinogenesis

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