Noncatalytic PTEN missense mutation predisposes to organ-selective cancer development in vivo

Enrico Caserta, Onur Egriboz, Hui Wang, Chelsea Martin, Christopher Koivisto, Thierry Pecót, Raleigh D. Kladney, Changxian Shen, Kang Sup Shim, Thac Pham, Matthew K. Karikomi, Melissa J. Mauntel, Sarmila Majumder, Maria C. Cuitino, Xing Tang, Arunima Srivastava, Lianbo Yu, Julie Wallace, Xiaokui Mo, Morag Park & 17 others Soledad A. Fernandez, Robert Pilarski, Krista M D La Perle, Thomas J. Rosol, Vincenzo Coppola, Diego H. Castrillon, Cynthia Timmers, David E. Cohn, David M. O’Malley, Floor Backes, Adrian A. Suarez, Paul Goodfellow, Helen M. Chamberlin, Erin R. Macrae, Charles L. Shapiro, Michael C. Ostrowski, Gustavo Leone

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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 (Pten<sup>FV</sup>), found in human cancer. Despite having reduced levels of PTEN protein, homozygous Pten<sup>FV/FV</sup> embryos have intact AKT signaling, develop normally, and are carried to term. Heterozygous Pten<sup>FV/+</sup> 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.

Original languageEnglish (US)
Pages (from-to)1707-1720
Number of pages14
JournalGenes and Development
Volume29
Issue number16
DOIs
StatePublished - Aug 15 2015

Fingerprint

Missense Mutation
Carcinoma
Neoplasms
PTEN Phosphohydrolase
Chromosomes, Human, Pair 10
Uterine Neoplasms
Adrenal Medulla
Human Mammary Glands
Adrenal Glands
Phenylalanine
Growth and Development
Phosphoric Monoester Hydrolases
Thymus Gland
Uterus
Prostate
Stomach
Thyroid Gland
Embryonic Structures

Keywords

  • Breast
  • Cancer
  • Endometrium
  • F341V
  • Pten
  • Uterus

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Caserta, E., Egriboz, O., Wang, H., Martin, C., Koivisto, C., Pecót, T., ... Leone, G. (2015). Noncatalytic PTEN missense mutation predisposes to organ-selective cancer development in vivo. Genes and Development, 29(16), 1707-1720. https://doi.org/10.1101/gad.262568.115

Noncatalytic PTEN missense mutation predisposes to organ-selective cancer development in vivo. / Caserta, Enrico; Egriboz, Onur; Wang, Hui; Martin, Chelsea; Koivisto, Christopher; Pecót, Thierry; Kladney, Raleigh D.; Shen, Changxian; Shim, Kang Sup; Pham, Thac; Karikomi, Matthew K.; Mauntel, Melissa J.; Majumder, Sarmila; Cuitino, Maria C.; Tang, Xing; Srivastava, Arunima; Yu, Lianbo; Wallace, Julie; Mo, Xiaokui; Park, Morag; Fernandez, Soledad A.; Pilarski, Robert; La Perle, Krista M D; Rosol, Thomas J.; Coppola, Vincenzo; Castrillon, Diego H.; Timmers, Cynthia; Cohn, David E.; O’Malley, David M.; Backes, Floor; Suarez, Adrian A.; Goodfellow, Paul; Chamberlin, Helen M.; Macrae, Erin R.; Shapiro, Charles L.; Ostrowski, Michael C.; Leone, Gustavo.

In: Genes and Development, Vol. 29, No. 16, 15.08.2015, p. 1707-1720.

Research output: Contribution to journalArticle

Caserta, E, Egriboz, O, Wang, H, Martin, C, Koivisto, C, Pecót, T, Kladney, RD, Shen, C, Shim, KS, Pham, T, Karikomi, MK, Mauntel, MJ, Majumder, S, Cuitino, MC, Tang, X, Srivastava, A, Yu, L, Wallace, J, Mo, X, Park, M, Fernandez, SA, Pilarski, R, La Perle, KMD, Rosol, TJ, Coppola, V, Castrillon, DH, Timmers, C, Cohn, DE, O’Malley, DM, Backes, F, Suarez, AA, Goodfellow, P, Chamberlin, HM, Macrae, ER, Shapiro, CL, Ostrowski, MC & Leone, G 2015, 'Noncatalytic PTEN missense mutation predisposes to organ-selective cancer development in vivo', Genes and Development, vol. 29, no. 16, pp. 1707-1720. https://doi.org/10.1101/gad.262568.115
Caserta E, Egriboz O, Wang H, Martin C, Koivisto C, Pecót T et al. Noncatalytic PTEN missense mutation predisposes to organ-selective cancer development in vivo. Genes and Development. 2015 Aug 15;29(16):1707-1720. https://doi.org/10.1101/gad.262568.115
Caserta, Enrico ; Egriboz, Onur ; Wang, Hui ; Martin, Chelsea ; Koivisto, Christopher ; Pecót, Thierry ; Kladney, Raleigh D. ; Shen, Changxian ; Shim, Kang Sup ; Pham, Thac ; Karikomi, Matthew K. ; Mauntel, Melissa J. ; Majumder, Sarmila ; Cuitino, Maria C. ; Tang, Xing ; Srivastava, Arunima ; Yu, Lianbo ; Wallace, Julie ; Mo, Xiaokui ; Park, Morag ; Fernandez, Soledad A. ; Pilarski, Robert ; La Perle, Krista M D ; Rosol, Thomas J. ; Coppola, Vincenzo ; Castrillon, Diego H. ; Timmers, Cynthia ; Cohn, David E. ; O’Malley, David M. ; Backes, Floor ; Suarez, Adrian A. ; Goodfellow, Paul ; Chamberlin, Helen M. ; Macrae, Erin R. ; Shapiro, Charles L. ; Ostrowski, Michael C. ; Leone, Gustavo. / Noncatalytic PTEN missense mutation predisposes to organ-selective cancer development in vivo. In: Genes and Development. 2015 ; Vol. 29, No. 16. pp. 1707-1720.
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abstract = "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.",
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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

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.

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KW - Endometrium

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