Skip to main content
Erschienen in: Virchows Archiv 6/2004

01.06.2004 | Original Article

Reduction of PTEN and p27kip1 expression correlates with tumor grade in prostate cancer. Analysis in radical prostatectomy specimens and needle biopsies

verfasst von: Tina Dreher, Hanswalter Zentgraf, Ulrich Abel, Alexandra Kappeler, Maurice S. Michel, Uwe Bleyl, Rainer Grobholz

Erschienen in: Virchows Archiv | Ausgabe 6/2004

Einloggen, um Zugang zu erhalten

Abstract

The extreme variability of prostate cancer implies latent disease with missing clinical symptoms in some cases. Tumor suppressors PTEN (phosphatase and tensin homolog deleted on chromosome ten) and p27kip1 are frequently mutated in various human cancers. PTEN negatively influences cell growth and induces apoptosis, while p27kip1 binds to cyclin-E-Cdk2 and counteracts mitosis. This study investigated the expression of PTEN and p27kip1 in prostatectomies and needle biopsies in order to determine whether protein localization or expression levels are correlated with tumor grade and whether PTEN and p27kip1 expression in biopsies are valuable predictive tumor markers. Analysis of PTEN demonstrated that weak expression levels were significantly more prevalent in high-grade tumors. Analysis of p27kip1 revealed that high-grade tumors had a higher percentage of cytoplasmic localization of the protein than low-grade tumors, where nuclear localization was more frequent. Furthermore, this study indicated a positive association between PTEN and p27kip1 levels. An increase of high-grade tumors corresponded to a progressive loss of both tumor suppressors in needle biopsies and prostatectomies. p27kip1 and PTEN did not show a higher predictive accuracy of the tumor grade in the surgical specimen than the Gleason score. However, p27kip1 had the same predictive value as the Gleason score in needle biopsies.
Literatur
1.
Zurück zum Zitat Catzavelos C, Bhattacharya N, Ung YC, Wilson JA, Roncari L, Sandhu C, Shaw P, Yeger H, Morava-Protzner I, Kapusta L (1997) Decreased levels of the cell-cycle inhibitor p27kip1 protein: prognostic implications in primary breast cancer. Nat Med 3:227–230PubMed Catzavelos C, Bhattacharya N, Ung YC, Wilson JA, Roncari L, Sandhu C, Shaw P, Yeger H, Morava-Protzner I, Kapusta L (1997) Decreased levels of the cell-cycle inhibitor p27kip1 protein: prognostic implications in primary breast cancer. Nat Med 3:227–230PubMed
2.
Zurück zum Zitat Dahia PL, Aguiar RC, Alberta J, Kum JB, Caron S, Sill H, Marsh DJ, Ritz J, Freedman A, Stiles C (1999) PTEN is inversely correlated with the cell survival factor Akt/PKB and is inactivated via multiple mechanisms in haematological malignancies. Hum Mol Genet 8:185–193CrossRefPubMed Dahia PL, Aguiar RC, Alberta J, Kum JB, Caron S, Sill H, Marsh DJ, Ritz J, Freedman A, Stiles C (1999) PTEN is inversely correlated with the cell survival factor Akt/PKB and is inactivated via multiple mechanisms in haematological malignancies. Hum Mol Genet 8:185–193CrossRefPubMed
3.
Zurück zum Zitat Di Cristofano A, Pandolfi PP (2000) The multiple roles of PTEN in tumor suppression. Cell 100:387–390PubMed Di Cristofano A, Pandolfi PP (2000) The multiple roles of PTEN in tumor suppression. Cell 100:387–390PubMed
4.
Zurück zum Zitat Di Cristofano A, De Acetis M, Koff A, Cordon-Cardo C, Pandolfi PP (2001) PTEN and p27kip1 cooperate in prostate cancer tumor suppression in the mouse. Nat Genet 27:222–224CrossRefPubMed Di Cristofano A, De Acetis M, Koff A, Cordon-Cardo C, Pandolfi PP (2001) PTEN and p27kip1 cooperate in prostate cancer tumor suppression in the mouse. Nat Genet 27:222–224CrossRefPubMed
5.
Zurück zum Zitat Dijkers PF, Medema RH, Pals C, Banerji L, Thomas NS, Lam EW, Burgering BM, Raaijmakers JA, Lammers JW, Koenderman L (2000) Forkhead transcription factor FKHR-L1 modulates cytokine-dependent transcriptional regulation of p27kip1. Mol Cell Biol 20:9138–9148CrossRefPubMed Dijkers PF, Medema RH, Pals C, Banerji L, Thomas NS, Lam EW, Burgering BM, Raaijmakers JA, Lammers JW, Koenderman L (2000) Forkhead transcription factor FKHR-L1 modulates cytokine-dependent transcriptional regulation of p27kip1. Mol Cell Biol 20:9138–9148CrossRefPubMed
6.
Zurück zum Zitat Freedland SJ, deGregorio F, Sacoolidge JC, Elshimali YI, Csathy GS, Dorey F, Reiter RE, Aronson WJ (2003) Preoperative p27kip1 status is an independent predictor of prostate specific antigen failure following radical prostatectomy. J Urol 169:1325–1330PubMed Freedland SJ, deGregorio F, Sacoolidge JC, Elshimali YI, Csathy GS, Dorey F, Reiter RE, Aronson WJ (2003) Preoperative p27kip1 status is an independent predictor of prostate specific antigen failure following radical prostatectomy. J Urol 169:1325–1330PubMed
7.
Zurück zum Zitat Gleason DF (1992) Histologic grading of prostate cancer: a perspective. Hum Pathol 23:273–279PubMed Gleason DF (1992) Histologic grading of prostate cancer: a perspective. Hum Pathol 23:273–279PubMed
8.
Zurück zum Zitat Hengst L, Reed SI (1996) Translational control of p27kip1 accumulation during the cell cycle. Science 271:1861–1864PubMed Hengst L, Reed SI (1996) Translational control of p27kip1 accumulation during the cell cycle. Science 271:1861–1864PubMed
9.
Zurück zum Zitat Jemal A, Momas A, Murray T, Thun M (2002) Cancer statistics, 2002. CA Cancer J Clin 52:23–47PubMed Jemal A, Momas A, Murray T, Thun M (2002) Cancer statistics, 2002. CA Cancer J Clin 52:23–47PubMed
10.
Zurück zum Zitat Kohler G, Milstein C (1975) Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256:495–497PubMed Kohler G, Milstein C (1975) Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256:495–497PubMed
11.
Zurück zum Zitat Kuczyk M, Machtens S (1999) Predictive value of decreased p27kip1 protein expression for the recurrence-free and long-term survival of prostate cancer patients. Br J Cancer 81:1052–1058CrossRefPubMed Kuczyk M, Machtens S (1999) Predictive value of decreased p27kip1 protein expression for the recurrence-free and long-term survival of prostate cancer patients. Br J Cancer 81:1052–1058CrossRefPubMed
12.
Zurück zum Zitat Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R (1997) PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275:1943–1947PubMed Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R (1997) PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275:1943–1947PubMed
13.
Zurück zum Zitat Liang J, Zubovitz J, Petrocelli T, Kotchetkov R, Connor MK, Han K, Lee JH, Ciarallo S, Catzavelos C, Beniston R (2002) PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nat Med 8:1153–1160CrossRefPubMed Liang J, Zubovitz J, Petrocelli T, Kotchetkov R, Connor MK, Han K, Lee JH, Ciarallo S, Catzavelos C, Beniston R (2002) PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nat Med 8:1153–1160CrossRefPubMed
14.
Zurück zum Zitat Liao Y, Grobholz R, Abel U, Trojan L, Michel MS, Angel P, Mayer D (2003) Increase of AKT/PKB expression correlates with Gleason pattern in human prostate cancer. Int J Cancer 107:676–680CrossRefPubMed Liao Y, Grobholz R, Abel U, Trojan L, Michel MS, Angel P, Mayer D (2003) Increase of AKT/PKB expression correlates with Gleason pattern in human prostate cancer. Int J Cancer 107:676–680CrossRefPubMed
15.
Zurück zum Zitat McMenamin ME, Soung P, Perera S, Kaplan I, Loda M, Sellers WR (1999) Loss of PTEN expression in paraffin-embedded primary prostate cancer correlates with high Gleason score and advanced stage. Cancer Res 59:4291–4296PubMed McMenamin ME, Soung P, Perera S, Kaplan I, Loda M, Sellers WR (1999) Loss of PTEN expression in paraffin-embedded primary prostate cancer correlates with high Gleason score and advanced stage. Cancer Res 59:4291–4296PubMed
16.
Zurück zum Zitat Mutter GL, Lin MC, Fitzgerald JT, Kum JB, Baak JP, Lees JA, Weng LP, Eng C (2000) Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J Natl Cancer Inst 92:924–930CrossRefPubMed Mutter GL, Lin MC, Fitzgerald JT, Kum JB, Baak JP, Lees JA, Weng LP, Eng C (2000) Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J Natl Cancer Inst 92:924–930CrossRefPubMed
17.
Zurück zum Zitat Nelen MR, van Staveren WC, Peeters EA, Hassel MB, Gorlin RJ, Hamm H, Lindboe CF, Fryns JP, Sijmons RH, Woods DG (1997) Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease. Hum Mol Genet 6:1383–1387PubMed Nelen MR, van Staveren WC, Peeters EA, Hassel MB, Gorlin RJ, Hamm H, Lindboe CF, Fryns JP, Sijmons RH, Woods DG (1997) Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease. Hum Mol Genet 6:1383–1387PubMed
18.
Zurück zum Zitat Ramaswarny S, Sellers WR (2000) PTEN: a prostate cancer tumor-suppressor gene. Prostate J 2:55–61CrossRef Ramaswarny S, Sellers WR (2000) PTEN: a prostate cancer tumor-suppressor gene. Prostate J 2:55–61CrossRef
19.
Zurück zum Zitat Ramaswamy S, Nakamura N, Vazquez F, Batt DB, Perera S, Roberts TM, Sellers WR (1999) Regulation of G1 progression by the PTEN tumor suppressor protein is linked to inhibition of the phosphatidylinositol 3-kinase/Akt pathway. Proc Natl Acad Sci U S A 96:2110–2115CrossRefPubMed Ramaswamy S, Nakamura N, Vazquez F, Batt DB, Perera S, Roberts TM, Sellers WR (1999) Regulation of G1 progression by the PTEN tumor suppressor protein is linked to inhibition of the phosphatidylinositol 3-kinase/Akt pathway. Proc Natl Acad Sci U S A 96:2110–2115CrossRefPubMed
20.
Zurück zum Zitat Reynisdottir I, Massague J (1997) The subcellular locations of p15(Ink4b) and p27(Kip1) coordinate their inhibitory interactions with cdk4 and cdk2. Genes Dev 11:492–503PubMed Reynisdottir I, Massague J (1997) The subcellular locations of p15(Ink4b) and p27(Kip1) coordinate their inhibitory interactions with cdk4 and cdk2. Genes Dev 11:492–503PubMed
21.
Zurück zum Zitat Rodier G, Montagnoli A, Di Marcotullio L, Coulombe P, Draetta GF, Pagano M, Meloche S (2001) p27 cytoplasmic localization is regulated by phosphorylation on Ser10 and is not a prerequisite for its proteolysis. EMBO J 20:6672–6682CrossRefPubMed Rodier G, Montagnoli A, Di Marcotullio L, Coulombe P, Draetta GF, Pagano M, Meloche S (2001) p27 cytoplasmic localization is regulated by phosphorylation on Ser10 and is not a prerequisite for its proteolysis. EMBO J 20:6672–6682CrossRefPubMed
22.
23.
Zurück zum Zitat Shin I, Yakes FM, Rojo F, Shin NY, Bakin AV, Baselga J, Arteaga CL (2002) PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kip1) at threonine 157 and modulation of its cellular localization. Nat Med 8:1145–1152CrossRefPubMed Shin I, Yakes FM, Rojo F, Shin NY, Bakin AV, Baselga J, Arteaga CL (2002) PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kip1) at threonine 157 and modulation of its cellular localization. Nat Med 8:1145–1152CrossRefPubMed
24.
Zurück zum Zitat Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Davis T (1997) Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 15:356–362PubMed Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Davis T (1997) Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 15:356–362PubMed
25.
Zurück zum Zitat Teng DH, Hu R, Lin H, Davis T, Iliev D, Frye C, Swedlund B, Hansen KL, Vinson VL, Gumpper KL (1997) MMAC1/PTEN mutations in primary tumor specimens and tumor cell lines. Cancer Res 57:5221–5225PubMed Teng DH, Hu R, Lin H, Davis T, Iliev D, Frye C, Swedlund B, Hansen KL, Vinson VL, Gumpper KL (1997) MMAC1/PTEN mutations in primary tumor specimens and tumor cell lines. Cancer Res 57:5221–5225PubMed
26.
Zurück zum Zitat True LD (1994) Surgical pathology examination of the prostate gland. Practice survey by American Society of Clinical Pathologists. Am J Clin Pathol 102:572–579PubMed True LD (1994) Surgical pathology examination of the prostate gland. Practice survey by American Society of Clinical Pathologists. Am J Clin Pathol 102:572–579PubMed
27.
Zurück zum Zitat Vazquez F, Grossman SR, Takahashi Y, Rokas MV, Nakamura N, Sellers WR (2001) Phosphorylation of the PTEN tail acts as an inhibitory switch by preventing its recruitment into a protein complex. J Biol Chem 276:48627–48630CrossRefPubMed Vazquez F, Grossman SR, Takahashi Y, Rokas MV, Nakamura N, Sellers WR (2001) Phosphorylation of the PTEN tail acts as an inhibitory switch by preventing its recruitment into a protein complex. J Biol Chem 276:48627–48630CrossRefPubMed
28.
Zurück zum Zitat Verbeke CS, Wenthe U, Grobholz R, Zentgraf H (2001) Fas ligand expression in Hodgkin lymphoma. Am J Surg Pathol 25:388–394PubMed Verbeke CS, Wenthe U, Grobholz R, Zentgraf H (2001) Fas ligand expression in Hodgkin lymphoma. Am J Surg Pathol 25:388–394PubMed
29.
Zurück zum Zitat Viglietto G, Motti ML, Bruni P, Melillo RM, D’Alessio A, Califano D, Vinci F, Chiappetta G, Tsichlis P, Bellacosa A (2002) Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer. Nat Med 8:1136–1144CrossRefPubMed Viglietto G, Motti ML, Bruni P, Melillo RM, D’Alessio A, Califano D, Vinci F, Chiappetta G, Tsichlis P, Bellacosa A (2002) Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27(Kip1) by PKB/Akt-mediated phosphorylation in breast cancer. Nat Med 8:1136–1144CrossRefPubMed
30.
Zurück zum Zitat Vis AN, Noordzij MA, Fitoz K, Wildhagen MF, Schroder FH, van der Kwast TH (2000) Prognostic value of cell cycle proteins p27(kip1) and MIB-1, and the cell adhesion protein CD44s in surgically treated patients with prostate cancer. J Urol 164:2156–2161CrossRefPubMed Vis AN, Noordzij MA, Fitoz K, Wildhagen MF, Schroder FH, van der Kwast TH (2000) Prognostic value of cell cycle proteins p27(kip1) and MIB-1, and the cell adhesion protein CD44s in surgically treated patients with prostate cancer. J Urol 164:2156–2161CrossRefPubMed
31.
Zurück zum Zitat Wu X, Senechal K, Neshat MS, Whang YE, Sawyers CL (1998) The PTEN/MMAC1 tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide 3-kinase/Akt pathway. Proc Natl Acad Sci U S A 95:15587–15591PubMed Wu X, Senechal K, Neshat MS, Whang YE, Sawyers CL (1998) The PTEN/MMAC1 tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide 3-kinase/Akt pathway. Proc Natl Acad Sci U S A 95:15587–15591PubMed
Metadaten
Titel
Reduction of PTEN and p27kip1 expression correlates with tumor grade in prostate cancer. Analysis in radical prostatectomy specimens and needle biopsies
verfasst von
Tina Dreher
Hanswalter Zentgraf
Ulrich Abel
Alexandra Kappeler
Maurice S. Michel
Uwe Bleyl
Rainer Grobholz
Publikationsdatum
01.06.2004
Verlag
Springer-Verlag
Erschienen in
Virchows Archiv / Ausgabe 6/2004
Print ISSN: 0945-6317
Elektronische ISSN: 1432-2307
DOI
https://doi.org/10.1007/s00428-004-1004-6

Weitere Artikel der Ausgabe 6/2004

Virchows Archiv 6/2004 Zur Ausgabe

Announcements

June 2004

Neu im Fachgebiet Pathologie

Molekularpathologische Untersuchungen im Wandel der Zeit

Open Access Biomarker Leitthema

Um auch an kleinen Gewebeproben zuverlässige und reproduzierbare Ergebnisse zu gewährleisten ist eine strenge Qualitätskontrolle in jedem Schritt des Arbeitsablaufs erforderlich. Eine nicht ordnungsgemäße Prüfung oder Behandlung des …

Vergleichende Pathologie in der onkologischen Forschung

Pathologie Leitthema

Die vergleichende experimentelle Pathologie („comparative experimental pathology“) ist ein Fachbereich an der Schnittstelle von Human- und Veterinärmedizin. Sie widmet sich der vergleichenden Erforschung von Gemeinsamkeiten und Unterschieden von …

Gastrointestinale Stromatumoren

Open Access GIST CME-Artikel

Gastrointestinale Stromatumoren (GIST) stellen seit über 20 Jahren ein Paradigma für die zielgerichtete Therapie mit Tyrosinkinaseinhibitoren dar. Eine elementare Voraussetzung für eine mögliche neoadjuvante oder adjuvante Behandlung bei …

Personalisierte Medizin in der Onkologie

Aufgrund des erheblichen technologischen Fortschritts in der molekularen und genetischen Diagnostik sowie zunehmender Erkenntnisse über die molekulare Pathogenese von Krankheiten hat in den letzten zwei Jahrzehnten ein grundlegender …