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Tumor Susceptibility of Rassf1a Knockout Mice

¹ Division of Biology and ² Department of Anatomic Pathology, City of Hope National Medical Center, Duarte, California; ³ Medizinische Fakultät, Martin-Luther-Universität Halle-Wittenberg, Halle/Saale, Germany; and ⁴ Department of Surgery, Washington University School of Medicine, St. Louis, Missouri

Requests for reprints: Gerd P. Pfeifer, Beckman Research Institute, City of Hope National Medical Center, 1450 East Duarte Road, Duarte, CA 91010. Phone: 626-301-8853; Fax: 626-930-5366. E-mail: gpfeifer{at}coh.org.

The human Ras association domain family 1 (RASSF1) gene is located at 3p21.3 in an area that is believed to harbor at least one important tumor suppressor gene. The two major isoforms of RASSF1, RASSF1A and RASSF1C, are distinguished by alternative NH₂-terminal exons and the two transcripts initiate in two separate CpG islands. RASSF1A is one of the most frequently inactivated genes described thus far in human solid tumors. Inactivation of RASSF1A most commonly involves methylation of the promoter and CpG island associated with the RASSF1A isoform. In contrast, RASSF1C is almost never inactivated in tumors. Here, we have derived Rassf1a knockout mice in which exon 1- of the Rassf1 gene was deleted, leading to specific loss of Rassf1a but not Rassf1c transcripts. Rassf1a-targeted mice were viable and fertile. Rassf1a^–/– mice were prone to spontaneous tumorigenesis in advanced age (18–20 months). Whereas only two tumors developed in 48 wild-type mice, six tumors were found in 35 Rassf1a^+/– mice (P < 0.05) and thirteen tumors were found in 41 Rassf1a^–/– mice (P < 0.001). The tumors in Rassf1a-targeted mice included lung adenomas, lymphomas, and one breast adenocarcinoma. Rassf1a^–/– and wild-type mice were treated with two chemical carcinogens, benzo(a)pyrene and urethane, to induce skin tumors and lung tumors, respectively. Rassf1a^–/– and Rassf1a^+/– mice showed increased tumor multiplicity and tumor size relative to control animals. The data are consistent with the tumor-suppressive role of Rassf1a, which may explain its frequent epigenetic inactivation in human tumors.

Key Words: RASSFIA • tumor suppressor • DNA methylation • gene targeting • lung cancer

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