1. ¹Cancer and Cell Biology Divison, Queensland Institute of Medical Research, Herston, Queensland, Australia
2. ²Department of Pathology, Peter MacCallum Cancer Institute, St Andrews Place, East Melbourne, Victoria, Australia
3. ³School of Medicine, University of Tasmania, Hobart, Tasmania, Australia

Correspondence: Professor NK Hayward, Queensland Institute of Medical Research, 300 Herston Rd, Herston, Queensland 4029, Australia. E-mail: Nick.Hayward@qimr.edu.au

⁴Current address: Wellcome Trust Centre for Human Genetics, University of Oxford ,Oxford OX1 2JD, UK

⁵Current address: Translational Genomics Research Institute, Phoenix, 85004 AZ, USA.

⁶Current address: Department of Pathology, Genentech Inc., San Francisco, 94080 CA, USA.

Received 17 August 2006; Revised 5 October 2006; Accepted 12 October 2006; Published online 18 December 2006.

Abstract

To identify possible genetic interactions between the mechanisms of tumor suppression of menin and pRb, we intercrossed mice with targeted deletions of Men1 and Rb1, and compared tumor development in cohorts of animals carrying single or dual mutations of these tumor-suppressor genes. In mice lacking one copy of Men1, pancreatic islet and anterior pituitary adenomas are common. In animals lacking one copy of Rb1, intermediate pituitary and thyroid tumors occur at high frequency, with less frequent development of pancreatic islet hyperplasia and parathyroid lesions. In mice heterozygous for both Men1 and Rb1, pancreatic hyperplasia and tumors of the intermediate pituitary and thyroid occurred at high frequency. Serum measurements of calcium and glucose did not vary significantly between genotypic groups. Loss of heterozygosity at the Rb1 locus was common in pituitary and thyroid tumors, whereas loss of menin was observed in pancreatic and parathyroid lesions. The tumor spectrum in the double heterozygotes was a combination of pathologies seen in each of the individual heterozygotes, without decrease in age of onset, indicating independent, non-additive effects of the two mutations. Together with the lack of increased tumor spectrum, this suggests that menin and pRb function in a common pathway of tumor suppression.