TY - JOUR
T1 - Irs2 inactivation suppresses tumor progression in Pten+/- mice
AU - Szabolcs, Matthias
AU - Keniry, Megan
AU - Simpson, Laura
AU - Reid, Latarsha J.
AU - Koujak, Susan
AU - Schiff, Sarah C.
AU - Davidian, Giselle
AU - Licata, Scott
AU - Gruvberger-Saal, Sofia
AU - Murty, Vundavalli V.V.S.
AU - Nandula, Subhadra
AU - Efstratiadis, Argiris
AU - Kushner, Jake A.
AU - White, Morris F.
AU - Parsons, Ramon
N1 - Funding Information:
Supported by the National Cancer Institute (Public Health Service grants CA082783 and CA099523 ); the Sands Family Foundation (to R.P.); and the National Institute of Diabetes, and Digestive and Kidney Diseases (grant DK43808 to M.F.W. ).
PY - 2009/1
Y1 - 2009/1
N2 - Mutations in the phosphatase and tensin homologue (PTEN)/ phosphatidylinositol-3 kinase-α (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.
AB - Mutations in the phosphatase and tensin homologue (PTEN)/ phosphatidylinositol-3 kinase-α (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.
UR - http://www.scopus.com/inward/record.url?scp=58249113832&partnerID=8YFLogxK
U2 - 10.2353/ajpath.2009.080086
DO - 10.2353/ajpath.2009.080086
M3 - Article
C2 - 19095950
AN - SCOPUS:58249113832
SN - 0002-9440
VL - 174
SP - 276
EP - 286
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 1
ER -