TY - JOUR
T1 - Noncatalytic PTEN missense mutation predisposes to organ-selective cancer development in vivo
AU - Caserta, Enrico
AU - Egriboz, Onur
AU - Wang, Hui
AU - Martin, Chelsea
AU - Koivisto, Christopher
AU - Pecót, Thierry
AU - Kladney, Raleigh D.
AU - Shen, Changxian
AU - Shim, Kang Sup
AU - Pham, Thac
AU - Karikomi, Matthew K.
AU - Mauntel, Melissa J.
AU - Majumder, Sarmila
AU - Cuitino, Maria C.
AU - Tang, Xing
AU - Srivastava, Arunima
AU - Yu, Lianbo
AU - Wallace, Julie
AU - Mo, Xiaokui
AU - Park, Morag
AU - Fernandez, Soledad A.
AU - Pilarski, Robert
AU - La Perle, Krista M D
AU - Rosol, Thomas J.
AU - Coppola, Vincenzo
AU - Castrillon, Diego H.
AU - Timmers, Cynthia
AU - Cohn, David E.
AU - O’Malley, David M.
AU - Backes, Floor
AU - Suarez, Adrian A.
AU - Goodfellow, Paul
AU - Chamberlin, Helen M.
AU - Macrae, Erin R.
AU - Shapiro, Charles L.
AU - Ostrowski, Michael C.
AU - Leone, Gustavo
N1 - Publisher Copyright:
© 2015 Caserta et al.
PY - 2015/8/15
Y1 - 2015/8/15
N2 - Inactivation of phosphatase and tensin homology deleted on chromosome 10 (PTEN) is linked to increased PI3K–AKT signaling, enhanced organismal growth, and cancer development. Here we generated and analyzed Pten knock-in mice harboring a C2 domain missense mutation at phenylalanine 341 (PtenFV), found in human cancer. Despite having reduced levels of PTEN protein, homozygous PtenFV/FV embryos have intact AKT signaling, develop normally, and are carried to term. Heterozygous PtenFV/+ mice develop carcinoma in the thymus, stomach, adrenal medulla, and mammary gland but not in other organs typically sensitive to Pten deficiency, including the thyroid, prostate, and uterus. Progression to carcinoma in sensitive organs ensues in the absence of overt AKT activation. Carcinoma in the uterus, a cancer-resistant organ, requires a second clonal event associated with the spontaneous activation of AKT and downstream signaling. In summary, this PTEN noncatalytic missense mutation exposes a core tumor suppressor function distinct from inhibition of canonical AKT signaling that predisposes to organ-selective cancer development in vivo.
AB - Inactivation of phosphatase and tensin homology deleted on chromosome 10 (PTEN) is linked to increased PI3K–AKT signaling, enhanced organismal growth, and cancer development. Here we generated and analyzed Pten knock-in mice harboring a C2 domain missense mutation at phenylalanine 341 (PtenFV), found in human cancer. Despite having reduced levels of PTEN protein, homozygous PtenFV/FV embryos have intact AKT signaling, develop normally, and are carried to term. Heterozygous PtenFV/+ mice develop carcinoma in the thymus, stomach, adrenal medulla, and mammary gland but not in other organs typically sensitive to Pten deficiency, including the thyroid, prostate, and uterus. Progression to carcinoma in sensitive organs ensues in the absence of overt AKT activation. Carcinoma in the uterus, a cancer-resistant organ, requires a second clonal event associated with the spontaneous activation of AKT and downstream signaling. In summary, this PTEN noncatalytic missense mutation exposes a core tumor suppressor function distinct from inhibition of canonical AKT signaling that predisposes to organ-selective cancer development in vivo.
KW - Breast
KW - Cancer
KW - Endometrium
KW - F341V
KW - Pten
KW - Uterus
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U2 - 10.1101/gad.262568.115
DO - 10.1101/gad.262568.115
M3 - Article
C2 - 26302789
AN - SCOPUS:84940092969
SN - 0890-9369
VL - 29
SP - 1707
EP - 1720
JO - Genes and Development
JF - Genes and Development
IS - 16
ER -