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Mouse Models in Tumor Suppression

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Mouse Models in Tumor Suppression Oncogene (1998) 17, 3385 ± 3400 ã 1998 Stockton Press All rights reserved 0950 ± 9232/98 $12.00 http://www.stockton-press.co.uk/onc Mouse models in tumor suppression Nader Ghebranious1 and Lawrence A Donehower*,1 Division of Molecular Virology and Department of Cell Biology, Baylor College of Medicine, Houston, Texas 77030, USA Genetic lesions found in tumors are often targeted to the by loss or mutation of the second allele in sporadically negative growth regulatory tumor suppressor genes. arising tumors. Inherited cancer predisposition syn- Much of our understanding of tumor suppressor gene dromes are often characterized by the germ line function is derived from experimental manipulations in transmission of a single defective tumor suppressor cultured cells. Recently, however, the generation of mice allele in the aected families. Not surprisingly, the with germ line tumor suppressor gene mutations through likelihood of an aected individual incurring a gene targeting in embryonic stem cells has provided mutation in the remaining wild type tumor suppressor another dimension by allowing experimental studies of allele and developing a tumor is much higher than for tumor suppressor function in an organismal context. the normal individual with two intact alleles. Novel insights into the role of tumor suppressors in The use of small animals for modeling tumors in a development, dierentiation, cell cycle control, and controlled experimental manner has been a mainstay of tumor suppression have been obtained from the studies cancer research for almost a century. However, the on these `knockout' mice. In addition, such mice may development of molecular genetic techniques to serve as disease models for humans with inherited cancer identify speci®c cancer-associated gene lesions, com- predisposition syndromes. Perhaps the greatest advan- bined with breakthroughs in the manipulation of the tage of many of the mouse tumor suppressor models is germ line of mice, have greatly facilitated the that they facilitate study of the roles of tumor suppressor generation of powerful new models for understanding gene loss in tumor initiation and progression in vivo. the mechanistic roles of speci®c genes in cancer Moreover, derivation of primary cells from tumor initiation and progression. The development of suppressor-de®cient mice has provided an important transgenic mice in the 1980s through zygote pro- resource for in vitro studies on the role of targeted nuclear injection methods has allowed the addition of genes in cell cycle regulation, DNA damage response, any cloned gene to the germ line of mice to determine regulation of apoptotic pathways, and preservation of the eects of the added gene on the resulting genomic stability. In this review, we discuss some of the phenotype (Palmiter and Brinster, 1986). Usually, the mechanistic insights provided by tumor suppressor- introduced exogenous gene is driven by a promoter de®cient mice and their utility as models for human which restricts expression of the transgene to a speci®c cancer syndromes. tissue compartment. This approach particularly lends itself to the analysis of the tumor promoting functions Keywords: tumor suppressors; knockout mice; cancer of dominant acting oncogenes, which can be expressed models; inherited cancer syndromes in speci®c tissues and might induce tumors within that tissue within a relatively short time frame (Hanahan, 1989). A large number of very useful mouse cancer models have been developed via this approach Introduction (Hanahan, 1989; Bedell et al., 1997). The recessive nature of tumor suppressors precluded Over the past twenty years, considerable progress has study of their in vivo eects through standard been achieved in understanding the molecular genetics transgenic approaches, however. Rather than constitu- of cancer formation. Genetic alterations in oncogenes tively expressing an activated oncogene, it would be and tumor suppressor genes occur consistently in many necessary to inactivate one or both endogenous tumor tumor types and experiments have shown that such suppressor alleles in order to study their role in cancer mutations can have a potent growth promoting eect. promotion. This was a more challenging task, but the Mutations in the oncogenes may constitutively activate development of mouse embryonic stem cell gene cellular proto-oncogenes so that they are refractory to targeting techniques has made such an approach regulation. The activated oncogene generally behaves feasible. Inactivation of endogenous tumor suppressor in a dominant manner in that its growth promoting genes in the germ line of mice has been achieved for eects can be maintained in the presence of a normal virtually every known tumor suppressor gene originally proto-oncogene allele. In contrast, tumor suppressor identi®ed in humans (Jacks, 1996; Bedell et al., 1997; mutations in tumors are recessive in nature. Inactiva- Venkatachalam and Donehower, 1998). tion or mutation of one allele is usually accompanied The advantages of such tumor suppressor `knock- out' mice have been multiple. First, the heterozygous version of a particular tumor suppressor knockout mouse may provide a useful animal model for the corresponding human cancer predisposition syndrome. While there have been a number of successes in this *Correspondence: LA Donehower, Division of Molecular Virology, One Baylor Plaza, Baylor College of Medicine, Houston, TX 77030, regard, the inherent dierences between mouse and USA human have resulted in some incongruities. For Mouse tumor suppressor models N Ghebranious and LA Donehower 3386 example, mice heterozygous for the Rb gene develop genes) are thought to increase genetic instability in a pituitary adenomas rather than the retinoblastomas manner which indirectly promotes cell growth through typically observed in children with a defective germ line an increased mutation rate. Our focus will be on the Rb allele (Jacks et al., 1992; Hu et al., 1994). gatekeeper genes associated with well characterized Nevertheless, the Rb heterozygous mice do develop inherited cancer predisposition syndromes in humans. early tumors and thus have provided a number of We will describe the tumor phenotypes observed in the important insights into the role of Rb in tumorigenesis. tumor suppressor-de®cient mice and we will assess the A second advantage provided by the homozygous usefulness of some of these tumor suppressor knockout knockout mice (and not obtainable by cell culture or mice as models for the corresponding human cancer human tumor studies) has been the important insights syndrome. It is not our intention to provide an into the role of tumor suppressors in embryonic exhaustive review, but rather to highlight some of the development. The well characterized embryology of the contributions that such mice have made to our basic mouse has facilitated these studies. With a few notable understanding of tumor suppressor function. exceptions, mice null for a given tumor suppressor exhibit embryonic lethality and a distinct pattern of organ malformations. Analysis of the biological and p53-de®cient mice (Li-Fraumeni syndrome) molecular bases of the observed defects has facilitated our understanding of the role of particular tumor Discovered in 1979 as a cellular protein complexed suppressor genes in organogenesis, regulation of cell with a DNA tumor virus oncoprotein (Lane and cycle control, dierentiation, and apoptosis. Crawford, 1979; Linzer and Levine, 1979), early The accumulation of numerous tumor-susceptible studies suggested that the p53 gene might encode a transgenic and knockout mice has aided investigators proto-oncogene, as mutant versions of p53 had in analysing genetic interactions among the oncogenes oncogenic activity in transformation assays (Jenkins and tumor suppressor genes. Intercrossing of two et al., 1984; Eliyahu et al., 1984; Parada et al., 1984). dierent tumor suppressor knockout mice to generate However, by 1989, several groups had demonstrated doubly de®cient ospring may reveal dierent levels of that the wild type p53 gene encodes a tumor suppressor cooperativity between the two genes. In some cases protein (Finlay et al., 1989; Eliyahu et al., 1989; Baker embryonic lethality in doubly de®cient mice can be et al., 1990; Chen et al., 1990; Mercer et al., 1990). accelerated or delayed. In other situations, tumor Transfection of p53 into cultured cells inhibited incidence rates can be accelerated and tumor spectra transformation mediated by a variety of oncogenes, altered by the combined tumor suppressor de®ciencies. while Vogelstein and others had shown that a number Important and sometimes surprising new insights can of human tumors displayed mutation or loss of both be obtained from such combinations. Crossing the p53 alleles (Masuda et al., 1987; Nigro et al., 1989; tumor suppressor mutations into inbred strains of Baker et al., 1989). The subsequent demonstration that dierent backgrounds has also revealed strain-speci®c a high fraction of individuals aected by a familial dierences in tumor development and spectra, allowing cancer predisposition called Li-Fraumeni syndrome for the identi®cation of novel tumor modi®er genes. had germ line p53 mutations solidi®ed the status of The identi®cation of such modi®ers (as well as other p53 as a tumor suppressor (Malkin et al., 1990; cooperating oncogenes and tumor suppressor genes) Srivastava et al., 1990). Since these initial reports, will be greatly assisted by the availability of thousands thousands of papers have been
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