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Inactivation of Conditional Rb by Villin-Cre Leads to Aggressive Tumors outside the Gastrointestinal Tract

¹ Harvard-Partners Center for Genetics and Genomics and ² Rodent Histopathology Core, Harvard Medical School; ³ Department of Pathology, Tufts University Schools of Medicine and Veterinary Medicine, Boston, Massachusetts

Requests for reprints: Melanie H. Kucherlapati, Harvard-Partners Center for Genetics and Genomics, Harvard Medical School, 77 Avenue Louis Pasteur, New Research Building 160B, Boston, MA 02115. Phone: 617-525-4438; Fax: 617-525-4435; E-mail: mkucherlapati{at}rics.bwh.harvard.edu.

We have crossed mice carrying the conditional Rb^tm2Brn allele with a constitutive Villin-Cre transgenic mouse. The Villin promoter in these animals is highly expressed in adult intestine and kidney proximal tubules and is expressed in the gut and nephros anlagen during embryogenesis. We report here that these mice develop tumors between 12 and 17 months old outside the gastrointestinal (GI) tract. A high penetrance of pituitary tumors and medullar carcinoma of the thyroid is observed with a lower incidence of hyperplasia of pulmonary neuroendocrine cells and aggressive liver, bile duct, stomach, oral cavity tumors, and lipomas. Rb rearrangement due to ectopic Villin promoter activity in neural crest or neural crest stem cells during embryogenesis is most likely responsible for the medullar carcinoma of the thyroid phenotype. The aggressive nature of the medullar carcinoma of the thyroid and its ability to metastasize to unusual sites make the model suitable for the study of tumor progression and mechanism of metastasis. Observed sites of metastasis include the stomach, small intestine, liver, lung, kidney, pancreas, spleen, bone marrow, salivary gland, fat, lymph nodes, and dorsal root ganglion. Because the Villin promoter is highly active throughout the GI and in the nephros anlagen during development, we find that Rb inactivation is not sufficient to initiate tumorigenesis in the GI or kidneys in mice. (Cancer Res 2006; 66(7): 3576-83)

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