Published online before print December 18, 2008

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(American Journal of Pathology. 2009;174:276-286.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080086

Irs2 Inactivation Suppresses Tumor Progression in Pten^+/– Mice

Matthias Szabolcs^*, Megan Keniry^*, Laura Simpson^*, Latarsha J. Reid^*, Susan Koujak^*, Sarah C. Schiff^*, Giselle Davidian^*, Scott Licata^*, Sofia Gruvberger-Saal^*, Vundavalli V.V.S. Murty^*, Subhadra Nandula^*, Argiris Efstratiadis^*, Jake A. Kushner, Morris F. White^¶ and Ramon Parsons^*

From the Institute for Cancer Genetics^* and the Departments of Pathology and Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, New York; the Division of Endocrinology, Children’s Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania; and the Division of Endocrinology,^¶ Howard Hughes Medical Institute, Children’s Hospital, Harvard Medical School, Boston, Massachusetts

Mutations in the phosphatase and tensin homologue (PTEN)/phosphatidylinositol-3 kinase- (PI3K) signaling pathway are frequently found in human cancer. In addition, Pten^+/– mice develop tumors in multiple organs because of the activation of the PI3K signaling cascade. Because activation of PI3K signaling leads to feedback inhibition of insulin receptor substrate-2 (IRS2) expression, an upstream activator of PI3K, we therefore anticipated that IRS2 expression would be low in tumors that lack PTEN. Surprisingly, however, an elevation of IRS2 was often detected in tumor samples in which PTEN levels were compromised. To determine the potential contribution of Irs2 to tumor progression, Pten^+/– mice were crossed with Irs2^+/– mice. Deletion of Irs2 did not affect the initiation of neoplasia found in Pten^+/– mice but suppressed cancer cell growth, proliferation, and invasion through the basement membrane. Deletion of Irs2 also attenuated the expression of Myc in prostatic intraepithelial neoplasia in Pten^+/– mice. In addition, the expression levels of IRS2 and MYC were highly correlated in human prostate cancer, and IRS2 could stimulate MYC expression in cultured cells. Our findings provide evidence that the PI3K-activating adaptor Irs2 contributes to tumor progression in Pten^+/– mice by stimulating both Myc and DNA synthesis.