Top

Published in:

01-04-2007 | Original Article

Prognostic value of PIK3CA and phosphorylated AKT expression in ovarian cancer

Authors: Joachim Woenckhaus, Klaus Steger, Klaus Sturm, Karsten Münstedt, Folker E. Franke, Irina Fenic

Published in: Virchows Archiv | Issue 4/2007

Abstract

Disrupted phosphatidylinositol 3-kinase (PI3K) activity and its effect on the downstream target AKT plays an important role in malignant diseases. Gain and/or amplification of PIK3CA gene, encoding the catalytic subunit of phosphatidylinositol 3-kinase (p110α) and its increased expression are associated with enhanced PI3K activity in ovarian cancer cell lines. In this study, ovarian carcinomas with documented clinical outcome were assessed for genetic aberrations at the 3q26.3 locus, including PIK3CA, by fluorescence in situ hybridization. PIK3CA amplification was evaluated by quantitative real-time PCR with respect to a control gene situated at 3q13. The expression of p110α, phosphorylated AKT (pAKT) and the proliferation marker Ki-67 were immunohistochemically investigated. PIK3CA amplification and Ki-67 index were strong predictors for an early tumour-associated death. p110α expression correlated with 3q26.3 gain and Ki-67 index but not with the patient outcome. No relationship could be observed between p110α and pAKT or between pAKT and disease outcome. It is interesting to note that cases with a nuclear pAKT immunoreactivity showed a trend of improved overall survival. Our results underline the prognostic significance of PIK3CA in ovarian carcinoma and argue against a simple linear model of PIK3CA gain/amplification followed by PI3K activation and consecutive AKT phosphorylation in ovarian carcinoma.

Andjelković M, Alessi DR, Meier R, Fernandez A, Lamb NJC, Frech M, Cron P, Cohen P, Lucocq JM, Hemmings BA (1997) Role of translocation in the activation and function of protein kinase B. J Biol Chem 272:31515–31524PubMedCrossRef

Arnold N, Hagele L, Walz L, Schempp W, Pfisterer J, Bauknecht T, Kiechle M (1996) Overrepresentation of 3q and 8q material and loss of 18q material are recurrent findings in advanced human ovarian cancer. Genes Chromosomes Cancer 16:46–54PubMedCrossRef

Campbell IG, Russell SE, Choong DC, Montgomery KG, Ciavarella ML, Hooi CSF, Cristiano BE, Pearson RB, Phillips WA (2004) Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res 64:7678–7681PubMedCrossRef

Cheng KW, Lahad JP, Kuo WL, Lapuk A, Yamada K, Auersperg N, Liu J, Smith-McCune K, Lu KH, Fishman D, Gray JW, Mills GB (2004) The RAB25 small GTPase determines aggressiveness of ovarian and breast cancers. Nat Med 10:1251–1256PubMedCrossRef

Diebold J (2001) Phenotype–genotype–correlation in ovarian neoplasia. Verh Dtsch Ges Pathol 85:153–160PubMed

Franke TF, Kaplan DR, Cantley LC (1997) PI3K: downstream AKTion blocks apoptosis. Cell 88:435–437PubMedCrossRef

Hauptmann S, Denkert C, Koch I, Petersen S, Schluns K, Reles A, Dietel M, Petersen I (2002) Genetic alterations in epithelial ovarian tumors analyzed by comparative genomic hybridization. Hum Pathol 30:632–641CrossRef

Iwabuchi H, Sakamoto M, Sakunaga H, Ma YY, Carcangiu ML, Pinkel D, Yang-Feng TL, Gray JW (1995) Genetic analysis of benign, low-grade, and high-grade ovarian tumors. Cancer Res 55:6172–6180PubMed

Kirkegaard T, Witton CJ, McGlynn LM, Tovey SM, Dunne B, Lyon A, Barlett JM (2005) AKT activation predicts outcome in breast cancer patients treated with tamoxifen. J Pathol 207:139–146PubMedCrossRef

10.

Lee KR, Tavassoli FA, Prat J, Dietel M, Gersell DJ, Karseladze AI, Hauptmann S, Rutgers J, Russell P, Buckley CH, Pisani P, Schwartz P, Goldgar DE, Silva E, Caduff R, Kubik-Huch RA (2003) Surface epithelial–stromal tumours. In: Fattaneh A, Devilee P (eds) World Health Organization and classification of tumours: pathology and genetics: tumours of the breast and female genital organs. IARC Press, Lyon, pp 113–197

11.

Lee S, Choi EJ, Jin C, Kim DH (2005) Activation of PI3K/Akt pathway by PTEN reduction and PIK3CA mRNA amplification contributes to cisplatin resistance in an ovarian cancer cell line. Gynecol Oncol 97:26–34PubMedCrossRef

12.

Lee WI, Bacchni P, Bertoni F, Maeng YH, Park YK (2004) Quantitative assessment of HER2/neu expression by real-time PCR and fluorescent in situ hybridization analysis in low-grade osteosarcoma. Oncol Rep 12:125–128PubMed

13.

Lin HK, Yeh S, Kang HY, Chang C (2001) Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor. Proc Natl Acad Sci USA 98:7200–7205PubMedCrossRef

14.

Luo J, Sobkiw CL, Logsdon NM, Watt JM, Signoretti S, O’Connell F, Shin E, Shim Y, Pao L, Neel BG, Depinho RA, Loda M, Cantley L (2005) Modulation of epithelial neoplasia and lymphoid hyperplasia in PTEN+/− mice by the p85 regulatory subunits of phosphoinositide 3-kinase. Proc Natl Acad Sci USA 19:10238–10243CrossRef

15.

Ma YY, Wei SJ, Lin YC, Lung JC, Chang TC, Whang-Peng JM, Liu JM, Yang DM, Yang WK, Shen CY (2000) PIK3CA as an oncogene in cervical cancer. Oncogene 19:2739–2744PubMedCrossRef

16.

Meier R, Alessi DR, Cron P, Andjelković M, Hemmings BA (1997) Mitogenic activation, phosphorylation, and nuclear translocation of protein kinase Bbeta. J Biol Chem 272:30491–30497PubMedCrossRef

17.

Munstedt K, Kovacic M, Zygmunt M, von Georgi R (2003) Impact of hemoglobin levels before and during chemotherapy on survival of patients with ovarian cancer. Int J Oncol 23:837–843PubMed

18.

Munstedt K, Steen J, Knauf AG, Buch T, von Georgi R, Franke FE (2000) Steroid hormone receptors and long term survival in invasive ovarian cancer. Cancer 15:1783–1791CrossRef

19.

Munstedt K, von Georgi R, Franke FE (2004) Correlation between MIB1-determined tumour growth fraction and incidence of tumour recurrence in early ovarian carcinomas. Cancer Invest 22:185–194PubMedCrossRef

20.

Osaki M, Oshimura M, Ito H (2004) PI3K–Akt pathway: its functions and alterations in human cancer. Apoptosis 9:667–676PubMedCrossRef

21.

Panigrahi AR, Pinder SE, Chan SY, Paish EC, Robertson JF, Ellis IO (2004) The role of PTEN and its signalling pathways, including AKT, in breast cancer; an assessment of relationships with other prognostic factors and with outcome. J Pathol 4:93–100CrossRef

22.

Qian J, Bostwick DG, Takahashi S, Borell TJ, Brown JA, Lieber MM, Jenkins RB (1996) Comparison of fluorescence in situ hybridization analysis of isolated nuclei and routine histological sections from paraffin-embedded prostatic adenocarcinoma specimens. Am J Pathol 194:1193–1199

23.

Scheid MP, Woodgett JR (2001) PKB/AKT: functional insights from genetic models. Nat Rev Mol Cell Biol 2:760–768PubMedCrossRef

24.

Schmitz KJ, Otterbach F, Callies R, Levkau B, Holscher M, Hoffmann O, Grabellus F, Kimming R, Schmidt KW, Baba HA (2004) Prognostic relevance of activated Akt kinase in node-negative breast cancer: a clinicopathological study of 99 cases. Mod Pathol 17:15–21PubMedCrossRef

25.

Sham JS, Tang TC, Fang Y, Sun L, Qin LX, Wu QL, Xie D, Guan XY (2002) Recurrent chromosome alterations in primary ovarian carcinoma in Chinese women. Cancer Genet Cytogenet 133:39–44PubMedCrossRef

26.

Shayesteh L, Lu Y, Kuo WL, Godfrey T, Collins C, Pinkel D, Powell B, Mills GB, Gray JW (1999) PIK3CA is implicated as an oncogene in ovarian cancer. Nat Genet 21:99–102PubMedCrossRef

27.

Shih IeM, Kurman R (2004) Ovarian tumourigenesis: a proposed model based on morphological and molecular genetic analysis. Am J Pathol 164:1511–1518PubMed

28.

Singh B, Stoffel A, Gogineni S, Poluri A, Pfister DG, Shaha AR, Pathak A, Bosl G, Cordon-Cardo C, Shah JP, Rao PH (2002) Amplification of the 3q26.3 locus is associated with progression to invasive cancer and is a negative prognostic factor in head and neck squamous cell carcinomas. Am J Pathol 161:365–371PubMed

29.

Slipicevic A, Holm R, Nguyen MT, Bohler PJ, Davidson B, Florenes VA (2005) Expression of activated Akt and PTEN in malignant melanomas: relationship with clinical outcome. Am J Clin Pathol 124:528–536PubMedCrossRef

30.

Sobin LH, Wittekind C (eds) (2002) TNM classification of malignant tumours, 6th edn. International Union Against Cancer, Wiley, New York

31.

Suzuki S, Moore DH 2nd, Ginzinger DG, Godfrey TE, Barclay J, Powell B, Pinkel D, Zaloudek C, Lu K, Mills G, Berchuck A, Gray JW (2000) An approach to analysis of large-scale correlations between genome changes and clinical endpoints in ovarian cancer. Cancer Res 60:5382–5385PubMed

32.

Van de Sande T, Roskams T, Lerut E, Joniau S, Van Poppel, Verhoeven G, Swinnen JV (2005) High-level expression of fatty acid synthase in human prostate cancer tissues is linked to activation and nuclear localization of Akt/PKB. J Pathol 206:214–219PubMedCrossRef

33.

Vogt PK, Jiang H, Aoki M (2005) Triple layer control: phosphorylation, acetylation and ubiquitination of FOXO proteins. Cell Cycle 4:908–913PubMed

34.

Wang Y, Kristensen GB, Helland A, Nesland JM, Borresen-Dale AL, Holm R (2005) Protein expression and prognostic value of genes in the erb-b signaling pathway in advanced ovarian carcinomas. Am J Clin Pathol 124:392–401PubMedCrossRef

35.

Woenckhaus J, Steger K, Werner E, Fenic I, Gamerdinger U, Dreyer T, Stahl U (2002) Genomic gain of PIK3CA and increased expression of p110alpha are associated with progression of dysplasia into invasive squamous cell carcinoma. J Pathol 198:335–342PubMedCrossRef

Title: Prognostic value of PIK3CA and phosphorylated AKT expression in ovarian cancer
Authors: Joachim Woenckhaus
Klaus Steger
Klaus Sturm
Karsten Münstedt
Folker E. Franke
Irina Fenic
Publication date: 01-04-2007
Publisher: Springer-Verlag
Published in: Virchows Archiv / Issue 4/2007
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI: https://doi.org/10.1007/s00428-006-0358-3

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Prognostic value of PIK3CA and phosphorylated AKT expression in ovarian cancer

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 4/2007

Study of the reactive dendritic cells in small B-cell lymphoproliferations of the skin

Expression of the breast differentiation antigen NY-BR-1 in a phyllodes tumor of the vulva

Molecular-cytogenetic characterisation of sex cord-stromal tumours: CGH analysis in sertoli cell tumours of the testis

Liver histology in patients with sporadic acute hepatitis E: a study of 11 patients from South-West France

Cytological diagnosis of malignant mesothelioma—improvement by additional analysis of hyaluronic acid in pleural effusions

Intestinal-type adenocarcinoma arising in a congenital sublingual teratoid cyst