Conditional Deletion of the LKB1 Gene in the Mouse Mammary Gland Induces Tumour Formation
A McCarthy, CJ Lord, K Savage, A Grigoriadis, DP Smith, B Weigelt, JS Reis-Filho, A Ashworth. ICR, London, United Kingdom; Ludwig Institute for Cancer Research, London, United Kingdom; Ludwig Institute for Cancer Research, Melbourne, Australia; Lawrence Berkeley National Laboratory, Berkeley
Background: Heterozygous germ-line mutations in the LKB1 (STK11) gene cause Peutz-Jeghers syndrome (PJS), an autosomal dominant disorder characterised by hamartomatous polyposis of the gastrointestinal tract and an increased risk of colorectal, breast, and other cancers. To specifically assess the effect of loss-of-function mutations upon mammary tumourigenesis we generated a mouse model bearing homozygous mutations of Lkb1 in the epithelial compartment of the mammary gland.
Design: We used gene targeting technology to generate a mouse strain in which the exons encoding the kinase domain of Lkb1 were flanked by loxP sites. Crossing of these mice to a strain expressing Cre recombinase in the mammary gland alone resulted in loxP mediated deletion and a gene encoding only the N-terminal 155 amino acids of the full-length (436 amino acid) protein, deleting 152 amino acids of the protein, including the kinase domain. Tumourigenesis was monitored in female mice. Mammary gland tumours were formalin fixed and subjected to immunohistochemical analysis using antibodies against oestrogen and progesterone receptors, HER2, cytokeratin 14 and p63. RNA was extracted from five tumours, which were snap frozen, and subjected to microarray analysis using the Mouse Sentrix-6 V1.1 BeadChip (Illumina).
Results: Mammary gland tumours developed in these mice with a latency of 46-85 weeks and occurred in the thoracic or inguinal glands. These tumours displayed histological features similar to those described in breast cancers arising in patients with PJS and were characterised as grade two invasive ductal carcinomas or solid papillary carcinomas. At the genomic level, these tumours consistently displayed a luminal phenotype. Ingenuity Pathway analysis revealed significant activation of cell cycle, cellular development and cancer networks, upregulation of cyclin D1 and activation of PI3K/AKT canonical pathway.
Conclusions: This mouse model of Lkb1 deficiency provides a potentially useful tool to investigate the role of Lkb1 in tumourigenesis and to guide the development of therapeutic approaches.
Monday, March 9, 2009 1:00 PM
Poster Session II # 60, Monday Afternoon