An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice

被引:189
作者
Kinross, Kathryn M. [1 ]
Montgomery, Karen G. [1 ]
Kleinschmidt, Margarete [1 ]
Waring, Paul [2 ]
Ivetac, Ivan [1 ]
Tikoo, Anjali [1 ]
Saad, Mirette [1 ,3 ]
Hare, Lauren [1 ,4 ]
Roh, Vincent [1 ]
Mantamadiotis, Theo [2 ]
Sheppard, Karen E. [1 ,3 ]
Ryland, Georgina L. [1 ,5 ]
Campbell, Ian G. [1 ,2 ]
Gorringe, Kylie L. [1 ,2 ]
Christensen, James G. [6 ]
Cullinane, Carleen [1 ,2 ]
Hicks, Rodney J. [1 ,7 ,10 ]
Pearson, Richard B. [1 ,3 ,4 ]
Johnstone, Ricky W. [1 ,2 ]
McArthur, Grant A. [1 ,2 ,7 ,9 ]
Phillips, Wayne A. [1 ,4 ,8 ,11 ]
机构
[1] Peter MacCallum Canc Ctr Peter Mac, Canc Res Div, Melbourne, Vic, Australia
[2] Univ Melbourne, Dept Pathol, Melbourne, Vic, Australia
[3] Univ Melbourne, Dept Biochem & Mol Biol, Melbourne, Vic, Australia
[4] Monash Univ, Dept Biochem & Mol Biol, Clayton, Vic, Australia
[5] Monash Univ, Monash Inst Med Res, Clayton, Vic, Australia
[6] Pfizer Global Res & Dev, La Jolla, CA USA
[7] Univ Melbourne, Dept Med, St Vincents Hosp, Melbourne, Vic, Australia
[8] Peter Mac, Canc Surg Div, Melbourne, Vic, Australia
[9] Peter Mac, Canc Med Div, Melbourne, Vic, Australia
[10] Peter Mac, Ctr Canc Imaging, Melbourne, Vic, Australia
[11] Univ Melbourne, St Vincents Hosp, Dept Surg, Melbourne, Vic, Australia
基金
瑞士国家科学基金会; 澳大利亚国家健康与医学研究理事会;
关键词
SURFACE EPITHELIUM; MOUSE MODEL; IN-VIVO; K-RAS; CANCER; EXPRESSION; GENE; PI3K; ADENOCARCINOMA; TRANSFORMATION;
D O I
10.1172/JCI59309
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Mutations in the gene encoding the p110 alpha subunit of PI3K (PIK3CA) that result in enhanced PI3K activity are frequently observed in human cancers. To better understand the role of mutant PIK3CA in the initiation or progression of tumorigenesis, we generated mice in which a PIK3CA mutation commonly detected in human cancers (the H1047R mutation) could be conditionally knocked into the endogenous Pik3ca locus. Activation of this mutation in the mouse ovary revealed that alone, Pik3ca(H1047R) induced premalignant hyperplasia of the ovarian surface epithelium but no tumors. Concomitantly, we analyzed several human ovarian cancers and found PIK3CA mutations coexistent with KRAS and/or PTEN mutations, raising the possibility that a secondary defect in a co-regulator of PI3K activity may be required for mutant PIK3CA to promote transformation. Consistent with this notion, we found that Pik3ca(H1047R) mutation plus Pten deletion in the mouse ovary led to the development of ovarian serous adenocarcinomas and granulosa cell tumors. Both mutational events were required for early, robust Akt activation. Pharmacological inhibition of PI3K/mTOR in these mice delayed tumor growth and prolonged survival. These results demonstrate that the Pik3ca(H1047R) mutation with loss of Pten is enough to promote ovarian cell transformation and that we have developed a model system for studying possible therapies.
引用
收藏
页码:553 / 557
页数:5
相关论文
共 50 条
  • [31] PIK3CA variants selectively initiate brain hyperactivity during gliomagenesis
    Yu, Kwanha
    Lin, Chia-Ching John
    Hatcher, Asante
    Lozzi, Brittney
    Kong, Kathleen
    Huang-Hobbs, Emmet
    Cheng, Yi-Ting
    Beechar, Vivek B.
    Zhu, Wenyi
    Zhang, Yiqun
    Chen, Fengju
    Mills, Gordon B.
    Mohila, Carrie A.
    Creighton, Chad J.
    Noebels, Jeffrey L.
    Scott, Kenneth L.
    Deneen, Benjamin
    NATURE, 2020, 578 (7793) : 166 - +
  • [32] Pilot investigation of the mutation profile of PIK3CA/PTEN genes (PI3K pathway) in grade 3 endometrial cancer
    Malentacchi, Francesca
    Turrini, Irene
    Sorbi, Flavia
    Projetto, Elisabetta
    Castiglione, Francesca
    Fambrini, Massimiliano
    Petraglia, Felice
    Pillozzi, Serena
    Noci, Ivo
    ONCOLOGY REPORTS, 2019, 41 (03) : 1560 - 1574
  • [33] Mouse models of PIK3CA mutations: one mutation initiates heterogeneous mammary tumors
    Koren, Shany
    Bentires-Alj, Mohamed
    FEBS JOURNAL, 2013, 280 (12) : 2758 - 2765
  • [34] PIK3CA Genotype and a PIK3CA Mutation-Related Gene Signature and Response to Everolimus and Letrozole in Estrogen Receptor Positive Breast Cancer
    Loi, Sherene
    Michiels, Stefan
    Baselga, Jose
    Bartlett, John M. S.
    Singhal, Sandeep K.
    Sabine, Vicky S.
    Sims, Andrew H.
    Sahmoud, Tarek
    Dixon, J. Michael
    Piccart, Martine J.
    Sotiriou, Christos
    PLOS ONE, 2013, 8 (01):
  • [35] A Novel PIK3CA Hotspot Mutation in Isfahanian Breast Cancer Patients
    Gharbi, Sedigheh
    Faghihi, Mehri
    Tavassoli, Manoochehr
    CANCER INVESTIGATION, 2011, 29 (04) : 313 - 317
  • [36] PIK3CA alterations in Middle Eastern ovarian cancers
    Abubaker, Jehad
    Bavi, Prashant
    Al-Haqawi, Wael
    Jehan, Zeenath
    Munkarah, Adnan
    Uddin, Shahab
    Al-Kuraya, Khawla S.
    MOLECULAR CANCER, 2009, 8
  • [37] Distinct β-Catenin and PIK3CA Mutation Profiles in Endometriosis-Associated Ovarian Endometrioid and Clear Cell Carcinomas
    Matsumoto, Toshihide
    Yamazaki, Masaaki
    Takahashi, Hiroyuki
    Kajita, Sabine
    Suzuki, Erina
    Tsuruta, Tomoko
    Saegusa, Makoto
    AMERICAN JOURNAL OF CLINICAL PATHOLOGY, 2015, 144 (03) : 452 - 463
  • [38] Impact of PIK3CA gain and PTEN loss on mantle cell lymphoma biology and sensitivity to targeted therapies
    Bettazova, Nardjas
    Senavova, Jana
    Kupcova, Kristyna
    Sovilj, Dana
    Rajmonova, Anezka
    Andera, Ladislav
    Svobodova, Karla
    Berkova, Adela
    Zemanova, Zuzana
    Daumova, Lenka
    Herman, Vaclav
    Davis, R. Eric
    Trneny, Marek
    Klener, Pavel
    Havranek, Ondrej
    Dolnikova, Alexandra
    BLOOD ADVANCES, 2024, 8 (20) : 5279 - 5289
  • [39] Insights into the mechanism of the PIK3CA E545K activating mutation using MD simulations
    Leontiadou, Hari
    Galdadas, Ioannis
    Athanasiou, Christina
    Cournia, Zoe
    SCIENTIFIC REPORTS, 2018, 8
  • [40] Novel Method for PIK3CA Mutation Analysis Locked Nucleic Acid-PCR Sequencing
    Ang, Daphne
    O'Gara, Rebecca
    Schilling, Amy
    Beadling, Carol
    Warrick, Andrea
    Troxell, Megan L.
    Corless, Christopher L.
    JOURNAL OF MOLECULAR DIAGNOSTICS, 2013, 15 (03) : 312 - 318