Key Points
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p27 (also known as KIP1, and encoded by CDKN1B) is regulated by multiple signal transduction pathways in normal and malignant cells.
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CDKN1B transcription can be regulated by the FoxO family and genetic defects that reduce CDKN1B transcription can predispose to multiple endocrine neoplasia (MEN)-like phenotypes.
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CDKN1B 5′UTR mediates its cell cycle-dependent translation and several proteins can bind the CDKN1B IRES to modulate its translation.
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micro-RNA-mediated inhibition of p27 translation emerges as a novel mechanism that can reduce p27 in some human cancers.
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p27 proteolysis is initiated by several different mechanisms.
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Tyrosine (Tyr) phosphorylation of p27 by Abl and Src family kinases reduces p27–CDK2 inhibition and transforms p27 from inhibitor to substrate of cyclin–CDK2 complexes.
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p27 phosphorylation at Thr157 and Thr198 by members of the AGC kinase family promotes assembly of p27–cyclin D–CDK4/6, but catalytic activation requires tyrosine phosphorylation.
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Cytoplasmic mislocalization of p27 is activated by AGC family kinases and contributes to RHOA inhibition and increased cell motility in cancers.
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p27 levels are reduced in the most common and lethal human epithelial cancers and this is associated with poor patient outcome.
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Restoration of p27 levels and/or nuclear localization may predict response to molecular therapies that target EGFR and IGFR families, MAP2K (also known as MEK), BCR-ABL and SRC.
Abstract
The cyclin-dependent kinase (Cdk) inhibitor p27 (also known as KIP1) regulates cell proliferation, cell motility and apoptosis. Interestingly, the protein can exert both positive and negative functions on these processes. Diverse post-translational modifications determine the physiological role of p27. Phosphorylation regulates p27 binding to and inhibition of cyclin–Cdk complexes, its localization and its ubiquitin-mediated proteolysis. In cancers, p27 is inactivated through impaired synthesis, accelerated degradation and by mislocalization. Moreover, studies in several tumour types indicate that p27 expression levels have both prognostic and therapeutic implications.
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References
Sherr, C. J. & Roberts, J. M. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 13, 1501–1512 (1999).
Hengst, L. & Reed, S. I. Inhibitors of the Cip/Kip family. Curr. Top. Microbiol. Immunol. 227, 25–41 (1998)
Nigg, E. A. Targets of cyclin-dependent protein kinases. Curr. Opin. Cell Biol. 199, 187–193 (1993).
James, M., Ray, A., Leznova, D. & Blain, S. W. Differential modification of p27Kip1 controls its cyclin D–cdk4 inhibitory activity. Mol. Cell Biol. (2007). Showed that p27 in active cyclin D1–CDK4 complexes is phosphorylated on tyrosine whereas p27 in catalytically inactive cyclin D1–CDK4 is not.
Grimmler, M. et al. Cdk-inhibitory activity and stability of p27Kip1 are directly regulated by oncogenic tyrosine kinases. Cell 128, 269–280 (2007).
Hengst, L. & Reed, S. I. Translational control of p27Kip1 accumulation during the cell cycle. Science 271, 1861–1864 (1996). This paper demonstrated that CDKN1B transcript levels vary little, but translation is maximal in quiescence and falls during G1 progression.
Liang, J. & Slingerland, J. M. Multiple roles of the PI3K/PKB (Akt) pathway in cell cycle progression. Cell Cycle 2, 339–345 (2003).
Besson, A., Assoian, R. K. & Roberts, J. M. Regulation of the cytoskeleton: an oncogenic function for CDK inhibitors? Nature Rev. Cancer 4, 948–955 (2004). An important review of primary work by these authors and others showing that cytoplasmic p27 has effects on cell motility that are, at least in part, independent of its Cdk regulatory functions.
Slingerland, J. & Pagano, M. Regulation of the cdk inhibitor p27 and its deregulation in cancer. J. Cell Physiol. 183, 10–17 (2000).
Medema, R. H., Kops, G. J., Bos, J. L. & Burgering, B. M. AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature 404, 782–787 (2000).
Dijkers, P. F. et al. Forkhead transcription factor FKHR-L1 modulates cytokine-dependent transcriptional regulation of p27KIP1. Mol. Cell. Biol. 20, 9138–9148 (2000). References 10 and 11 were the first to show that p27 transcription is opposed by Akt action on forkhead transcription factors.
Trotman, L. C. et al. Identification of a tumour suppressor network opposing nuclear Akt function. Nature 441, 523–527 (2006).
Yang, H. L., Zhao, R. Y., Yang, H. Y. & Lee, M. H. Constitutively active FOXO4 inhibits Akt activity, regulates p27 Kip1 stability, and suppresses HER2-mediated tumorigenicity. Oncogene 24, 1924–1935 (2005).
Wang, X. H. et al. Increased hepatic forkhead box M1B (FoxM1B) levels in old-aged mice stimulated liver regeneration through diminished p27(KiP1) protein levels and increased Cdc25B expression. J. Biol. Chem. 277, 44310–44316 (2002).
Karnik, S. K. et al. Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27(Kip1) and p18(INK4c). Proc. Natl Acad. Sci. USA 102, 14659–14664 (2005).
Fontaniere, S., Casse, H., Bertolino, P. & Zhang, C. X. Analysis of p27Kip1 expression in insulinomas developed in pancreatic β-cell specific Men1 mutant mice. Familial Cancer 5, 49–54 (2006).
Pellegata, N. S. et al. Germ-line mutations in p27Kip1 cause a multiple endocrine neoplasia syndrome in rats and humans. Proc. Natl Acad. Sci. USA 103, 15558–15563 (2006).
Georgitsi, M. et al. Mutation analysis of aryl hydrocarbon receptor interacting protein (AIP) gene in colorectal, breast, and prostate cancers. Br. J. Cancer 96, 352–356 (2007).
Yang, W. et al. Repression of transcription of the p27Kip1 cyclin-dependent kinase inhibitor gene by c-Myc. Oncogene 20, 1688–1702 (2001).
O'Hagan, R. C. et al. Myc-enhanced expression of Cul1 promotes ubiquitin-dependent proteolysis and cell cycle progression. Genes Dev. 14, 2185–2191 (2000).
Keller, U. B. et al. Myc targets Cks1 to provoke the suppression of p27Kip1, proliferation and lymphomagenesis. EMBO J. 26, 2562–2574 (2007).
Wang, C. G. et al. Activation of p27Kip1 expression by E2F1 — a negative feedback mechanism. J. Biol. Chem. 280, 12339–12343 (2005).
Inoue, T., Kamiyama, J. & Sakai, T. Sp1 and NF-Y synergistically mediate the effect of vitamin D-3 in the p27Kip1 gene promoter that lacks vitamin D response elements. J. Biol. Chem. 274, 32309–32317 (1999).
Murata, K. et al. Hes1 directly controls cell proliferation through the transcriptional repression of p27Kip1. Mol. Cell. Biol. 25, 4262–4271 (2005).
Huang, Y. C., Chen, J. Y. & Hung., W. C. Vitamin D-3 receptor/Sp1 complex is required for the induction of p27Kip1 expression by vitamin D-3. Oncogene 23, 4856–4861 (2004).
Agrawal, D. et al. Repression of p27kip1 synthesis by platelet-derived growth factor in BALB/c 3T3 cells. Mol. Cell Biol. 16, 4327–4336 (1996).
Millard, S. S. et al. Enhanced ribosomal association of p27Kip1 mRNA is a mechanism contributing to accumulation during growth arrest. J. Biol. Chem. 272, 7093–7098 (1997).
Gopfert, U., Kullmann, M. & Hengst, L. Cell cycle-dependent translation of p27 involves a responsive element in its 5′-UTR that overlaps with a uORF. Hum. Mol. Genet. 12, 1767–1779 (2003).
Miskimins, W. K., Wang, G., Hawkinson, M. & Miskimins, R. Control of cyclin-dependent kinase inhibitor p27 expression by cap-independent translation. Mol. Cell. Biol. 21, 4960–4967 (2001).
Kullmann, M., Gopfert, U., Siewe, B. & Hengst, L. ELAV/Hu proteins inhibit p27 translation via an IRES element in the p27 5′ UTR. Genes Dev. 16, 3087–3099 (2002). Showed ELAV /Hu proteins bind an IRES in the 5′ UTR to impair p27 translation. Overexpression of ELAV in cancers might reduce p27 translation and contribute to development or progression of certain cancers.
Yoon, A. et al. Impaired control of IRES-mediated translation in X-linked dyskeratosis congenita. Science 312, 902–906 (2006).
Cho, S. C., Kim, J. H., Back, S. H. & Jang, S. K. Polypyrimidine tract-binding protein enhances the internal ribosomal entry site-dependent translation of p27Kip1 mRNA and modulates transition from G1 to S phase. Mol. Cell. Biol. 25, 1283–1297 (2005).
Millard, S. S., Vidal, A., Markus, M. & Koff, A. A U-rich element in the 5′ untranslated region is necessary for the translation of p27 mRNA. Mol. Cell Biol. 20, 5947–5959 (2000).
Erkinheimo, T. L. et al. Cytoplasmic HuR expression correlates with poor outcome and with cyclooxygenase 2 expression in serous ovarian carcinoma. Cancer Res. 63, 7591–7594 (2003).
Denkert, C. et al. Overexpression of the embryonic-lethal abnormal vision-like protein HuR in ovarian carcinoma is a prognostic factor and is associated with increased cyclooxygenase 2 expression. Cancer Res. 64, 189–195 (2004).
de Silanes, I. L. et al. Role of the RNA-binding protein HuR in colon carcinogenesis. Oncogene 22, 7146–7154 (2003).
Vidal, A., Millard, S. S., Miller, J. P. & Koff, A. Rho activity can alter the translation of p27 mRNA and is important for RasV12-induced transformation in a manner dependent on p27 status. J. Biol. Chem. 277, 16433–16440 (2002).
Gonzalez, T. et al. Inhibition of Cdk4 activity enhances translation of p27kip1 in quiescent Rb-negative cells. J. Biol. Chem. 278, 12688–12695 (2003).
le Sage, C., Nagel, R. & Agami, R. Diverse ways to control p27Kip1 function: miRNAs come into play. Cell Cycle 6, 2742–2749 (2007). Important recent review of work by these authors and others showing that p27 translation is reduced by miRNA-221/222 and might contribute to p27 loss in human cancer.
Kedde, M. et al. RNA-binding protein Dnd1 inhibits microRNA access to target mRNA. Cell 131, 1273–1286 (2007).
Galardi, S. et al. miR-221 and miR-222 expression affects the proliferation potential of human prostate carcinoma cell lines by targeting p27Kip1. J. Biol. Chem. 282, 23716–23724 (2007).
Volinia, S. et al. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc. Natl Acad. Sci. USA 103, 2257–2261 (2006).
Visone, R. et al. MicroRNAs (miR)-221 and miR-222, both overexpressed in human thyroid papillary carcinomas, regulate p27Kip1 protein levels and cell cycle. Endocr. Relat. Cancer 14, 791–798 (2007).
Calin, G. A. et al. A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N. Engl. J. Med. 353, 1793–1801 (2005). References 42–44 and others within reference 38 demonstrate overexpression of miRNA-221/222 in human neoplasia.
Nakayama, K. I. & Nakayama, K. Ubiquitin ligases: cell-cycle control and cancer. Nature Rev. Cancer 6, 369–381 (2006). Important review of primary work by these authors and others that covers proteolytic mechanisms governing p27 degradation.
Bloom, J. & Pagano, M. Deregulated degradation of the cdk inhibitor p27 and malignant transformation. Semin. Cancer Biol. 13, 41–47 (2003). Important conceptual review of p27 proteolysis by the SCFSKP2 ubiquitin ligase pathway.
Sabile, A. et al. Regulation of p27 degradation and S-phase progression by Ro52 RING finger protein. Mol. Cell. Biol. 26, 5994–6004 (2006).
Pavletich, N. P. Mechanisms of cyclin-dependent kinase regulation: structures of Cdks, their cyclin activators, and Cip and INK4 inhibitors. J. Mol. Biol. 287, 821–828 (1999).
Chu, I. et al. p27 phosphorylation by Src regulates inhibition of cyclin E–Cdk2. Cell 128, 281–294 (2007). References 5 and 49 first showed that tyrosine phosphorylation of p27 has effects on Cdk binding and promotes SCFSKP2-mediated p27 proteolysis.
Russo, A. A., Jeffrey, P. D., Patten, A. K., Massague, J. & Pavletich, N. P. Crystal structure of the p27Kip1 cyclin-dependent-kinase inhibitor bound to the cyclin A-Cdk2 complex. Nature 382, 325–331 (1996). Solved the crystal structure of the N-terminal fragment of p27 bound to cyclin A–CDK2.
Malek et al. A mouse knock-in model exposes sequential proteolytic pathways that regulate p27Kip1 in G1 and S phase. Nature 413, 323–327 (2001)
Bondar, T. et al. Cu14A and DDB1 associate with Skp2 to target p27Kip1 for proteolysis involving the COP9 signalosome. Mol. Cell. Biol. 26, 2531–2539 (2006).
Tomoda, K., Kubota, Y. & Kato, J. Degradation of the cyclin-dependent-kinase inhibitor p27Kip1 is instigated by Jab1. Nature 398, 160–165 (1999). References 52 & 53 indicate that p27 proteolysis might be linked to COP9 signalosome function.
Boehm, M. et al. A growth factor-dependent nuclear kinase phosphorylates p27(Kip1) and regulates cell cycle progression. EMBO J. 21, 3390–3401 (2002).
Deng, X., Mercer, S. E., Shah, S., Ewton, D. Z. & Friedman, E. The cyclin-dependent kinase inhibitor p27Kip1 is stabilized in G0 by Mirk/dyrk1B kinase. J. Biol. Chem. 279, 22498–22504 (2004).
Rodier, G. et al. p27 cytoplasmic localization is regulated by phosphorylation on Ser10 and is not a prerequisite for its proteolysis. EMBO J. 20, 6672–6682 (2001).
Ishida, N. et al. Phosphorylation of p27Kip1 on serine 10 is required for its binding to CRM1 and nuclear export. J. Biol. Chem. 277, 14355–14358 (2002).
Connor, M. K. et al. CRM1/Ran-mediated nuclear export of p27Kip1 involves a nuclear export signal and links p27 export and proteolysis. Mol. Biol. Cell 14, 201–213 (2003). References 56–58 demonstrate that p27 is exported from the nucleus in a CRM1-dependent manner and show serine 10 phosphorylation promotes nuclear export.
Besson, A. et al. A pathway in quiescent cells that controls p27Kip1 stability, subcellular localization, and tumor suppression. Genes Dev. 20, 47–64 (2006). This paper showed that serine 10 phosphorylation regulates p27 stability in G0.
Liang, J. et al. The energy sensing LKB-1–AMPK pathway regulates p27kip1 phosphorylation mediating the decision to enter autophagy or apoptosis. Nature Cell Biol. 9, 218–224 (2007).
Kossatz, U. et al. C-terminal phosphorylation controls the stability and function of p27kip1. EMBO J. 25, 5159–5170 (2006).
Kotake, Y., Nakayama, K., Ishida, N. & Nakayama, K. I. Role of serine 10 phosphorylation in p27 stabilization revealed by analysis of p27 knock-in mice harboring a serine 10 mutation. J. Biol. Chem. 280, 1095–1102 (2005). This paper showed that serine 10 phosphorylation regulates p27 stability in G0.
Ishizawar, R. & Parsons, S. J. c-Src and cooperating partners in human cancer. Cancer Cell 6, 209–214 (2004).
Pegram, M. D., Pauletti, G. & Slamon, D. J. HER-2/neu as a predictive marker of response to breast cancer therapy. Breast Cancer Res. Treat. 52, 65–77 (1998).
Arteaga, C. L. & Baselga, J. Clinical trial design and end points for epidermal growth factor receptor-targeted therapies: implications for drug development and practice. Clin. Cancer Res. 9, 1579–1589 (2003).
Spataro, V. J. et al. Decreased immunoreactivity for p27 protein in patients with early-stage breast carcinoma is correlated with HER-2/neu overexpression and with benefit from one course of perioperative chemotherapy in patients with negative lymph node status: results from International Breast Cancer Study Group Trial, V. Cancer 97, 1591–1600 (2003).
Newman, L. et al. Correlation of p27 protein expression with HER-2/neu expression in breast cancer. Mol. Carcinog. 30, 169–175 (2001).
Donovan, J. C., Milic, A. & Slingerland, J. M. Constitutive MEK/MAPK activation leads to p27Kip1 deregulation and antiestrogen resistance in human breast cancer cells. J. Biol. Chem. 276, 40888–40895 (2001).
Yang, H. Y., Zhou, B. P., Hung., M. C. & Lee, M. H. Oncogenic signals of HER-2/neu in regulating the stability of the cyclin-dependent kinase inhibitor p27. J. Biol. Chem. 275, 24735–24739 (2000). This paper demonstrated that p27 proteolysis is activated by overexpression of Her2.
Nahta, R., Takahashi, T., Ueno, N. T., Hung., M. C. & Esteva, F. J. P27kip1 down-regulation is associated with trastuzumab resistance in breast cancer cells. Cancer Res. 64, 3981–3986 (2004).
Busse, D. et al. Reversible G1 arrest induced by inhibition of the epidermal growth factor receptor tyrosine kinase requires up-regulation of p27KIP1 independent of MAPK activity. J. Biol. Chem. 275, 6987–6995 (2000).
Chu, I., Blackwell, K., Chen, S. & Slingerland, J. The dual ErbB1/ErbB2 inhibitor, lapatinib (GW572016), cooperates with tamoxifen to inhibit both cell proliferation- and estrogen-dependent gene expression in antiestrogen-resistant breast cancer. Cancer Res. 65, 18–25 (2005).
Moller, M. B., Skjodt, K., Mortensen, L. S. & Pedersen, N. T. Clinical significance of cyclin-dependent kinase inhibitor p27Kip1 expression and proliferation in non-Hodgkin's lymphoma: independent prognostic value of p27Kip1. Br. J. Haematol. 105, 730–736 (1999).
Tsihlias, J., Kapusta, L. & Slingerland, J. The prognostic significance of altered cyclin-dependent kinase inhibitors in human cancer. Annu. Rev. Med. 50, 401–423 (1999).
Andreu, E. J. et al. BCR-ABL induces the expression of Skp2 through the PI3K pathway to promote p27Kip1 degradation and proliferation of chronic myelogenous leukemia cells. Cancer Res. 65, 3264–3272 (2005).
Donato, N. J. et al. BCR–ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood 101, 690–698 (2003).
Vivanco, I. & Sawyers, C. L. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nature Rev. Cancer 2, 489–501 (2002).
Tsutsui, S. et al. Inactivation of PTEN is associated with a low p27Kip1 protein expression in breast carcinoma. Cancer 104, 2048–2053 (2005).
Latres, E. et al. Role of the F-box protein Skp2 in lymphomagenesis. Proc. Natl Acad. Sci. USA 98, 2515–2520 (2001). First demonstration that SKP2 is overexpressed in human lymphoma and that SKP2 overexpression promotes lymphoma progression in a mouse model in vivo.
Chiarle, R. et al. Increased proteasome degradation of cyclin-dependent kinase inhibitor p27 is associated with a decreased overall survival in mantle cell lymphoma. Blood 95, 619–626 (2000).
Hershko, D. et al. Inverse relation between levels of p27Kip1 and of its ubiquitin ligase subunit Skp2 in colorectal carcinomas. Cancer 91, 1745–1751 (2001).
Shapira, M. et al. The prognostic impact of the ubiquitin ligase subunits Skp2 and Cks1 in colorectal carcinoma. Cancer 103, 1336–1346 (2005).
Signoretti, S. et al. Oncogenic role of the ubiquitin ligase subunit Skp2 in human breast cancer. J. Clin. Invest. 110, 633–641 (2002).
Shintani, S. et al. Skp2 and Jab1 expression are associated with inverse expression of p27KIP1 and poor prognosis in oral squamous cell carcinomas. Oncology 65, 355–362 (2003).
Kudo, Y. et al. High expression of S-phase kinase-interacting protein 2, human F-box protein, correlates with poor prognosis in oral squamous cell carcinomas. Cancer Res. 61, 7044–7047 (2001).
Gstaiger, M. et al. Skp2 is oncogenic and overexpressed in human cancers. Proc. Natl Acad. Sci. USA 98, 5043–5048 (2001). First demonstrated overexpression and oncogenicity of SKP2 in human epithelial cancer.
Drobnjak, M. et al. Altered expression of p27 and Skp2 proteins in prostate cancer of African-American patients. Clin. Cancer Res. 9, 2613–2619 (2003).
Yokoi, S. et al. A novel target gene, SKP2, within the 5p13 amplicon that is frequently detected in small cell lung cancers. Am. J. Pathol. 161, 207–216 (2002).
Masuda, T. A. et al. Clinical and biological significance of S-phase kinase-associated protein 2 (Skp2) gene expression in gastric carcinoma: modulation of malignant phenotype by Skp2 overexpression, possibly via p27 proteolysis. Cancer Res. 62, 3819–3825 (2002).
Nakayama, K. et al. Skp2-mediated degradation of p27 regulates progression into mitosis. Dev. Cell 6, 661–672 (2004).
Kossatz, U. et al. Skp2-dependent degradation of p27kip1 is essential for cell cycle progression. Genes Dev. 18, 2602–2607 (2004).
Catzavelos, C. et al. Decreased levels of the cell-cycle inhibitor p27Kip1 protein: prognostic implications in primary breast cancer. Nature Med. 3, 227–230 (1997).
Porter, P. L. et al. Expression of cell cycle regulators p27kip1 and cyclin E, alone and in combination, correlate with survival in young breast cancer patients. Nature Med. 3, 222–225 (1997).
Tan, P. et al. The cell cycle inhibitor p27 is an independent prognostic marker in small (T1a, b) invasive breast carcinomas. Cancer Res. 57, 1259–1263 (1997). References 92–94 were the first to demonstrate that p27 levels are frequently reduced in human breast cancer and that this is prognostic for poor patient outcome on multivariate analysis.
Zeng, Y., Hirano, K., Hirano, M., Nishimura, J. & Kanaide, H. Minimal requirements for the nuclear localization of p27Kip1, a cyclin-dependent kinase inhibitor. Biochem. Biophys. Res. Commun. 274, 37–42 (2000).
LaBaer, J. et al. New functional activities for the p21 family of CDK inhibitors. Genes Dev. 11, 847–862 (1997).
Cheng, M. et al. The p21Cip1 and p27Kip1 CDK 'inhibitors' are essential activators of cyclin D-dependent kinases in murine fibroblasts. EMBO J. 18, 1571–1583 (1999). References 96 and 97 provide biochemical and genetic evidence that p27 and p21 regulate the assembly of D-type cyclin–Cdk complexes.
Liang, J. et al. PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27-mediated G1 arrest. Nature Med. 8, 1153–1160 (2002). This paper showed that Akt phosphorylated p27 to impair its nuclear import.
Shin, I., Rotty, J., Wu, F. Y. & Arteaga, C. L. Phosphorylation of p27Kip1 at Thr-157 interferes with its association with importin alpha during G1 and prevents nuclear re-entry. J. Biol. Chem. 280, 6055–6063 (2005).
Sekimoto, T., Fukumoto, M. & Yoneda, Y. 14-3-3 suppresses the nuclear localization of threonine 157-phosphorylated p27Kip1. EMBO J. 23, 1934–1942 (2004).
Fujita, N., Sato, S., Katayama, K. & Tsuruo, T. Akt-dependent phosphorylation of p27Kip1 promotes binding to 14-3-3 and cytoplasmic localization. J. Biol. Chem. 277, 28706–28713 (2002).
Fujita, N., Sato, S. & Tsuruo, T. Phosphorylation of p27Kip1 at threonine 198 by p90 ribosomal protein S6 kinases promotes its binding to 14-3-3 and cytoplasmic localization. J. Biol. Chem. 278, 49254–49260 (2003).
Kardinal, C. et al. Tyrosine phosphorylation modulates binding preference to cyclin-dependent kinases and subcellular localization of p27Kip1 in the acute promyelocytic leukemia cell line NB4. Blood 107, 1133–1140 (2006).
Soos, T. J. et al. Formation of p27–CDK complexes during the human mitotic cell cycle. Cell Growth Differ. 7, 135–146 (1996).
Zhang, H., Hannon, G. & Beach, D. p21-containing cyclin kinases exist in both active and inactive states. Genes Dev. 8, 1750–1758 (1994).
Nagahara, H. et al. Transduction of full-length TAT fusion proteins into mammalian cells: TAT–p27Kip1 induces cell migration. Nature Med. 4, 1449–1452 (1998).
Cheng, M., Sexl, V., Sherr, C. J. & Roussel, M. F. Assembly of cyclin D-dependent kinase and titration of p27Kip1 regulated by mitogen-activated protein kinase kinase (MEK1). Proc. Natl Acad. Sci. USA. 95, 1091–1096 (1998).
Liu, X. et al. Disruption of TGF-β growth inhibition by oncogenic ras is linked to p27Kip1 mislocalization. Oncogene 19, 5926–5935 (2000).
Viglietto, G. et al. Cytoplasmic relocalization and inhibition of the cyclin-dependent kinase inhibitor p27Kip1 by PKB/Akt-mediated phosphorylation in breast cancer. Nature Med. 8, 1136–1144 (2002).
Shin, I. et al. PKB/Akt mediates cell-cycle progression by phosphorylation of p27Kip1 at threonine 157 and modulation of its cellular localization. Nature Med. 8, 1145–1152 (2002). References 98, 109 and 110 were published together and all showed that cytoplasmic mislocalization of p27 in human breast cancer was associated with activation of Akt.
Viglietto, G. & Fusco, A. Understanding p27kip1 deregulation in cancer: down-regulation or mislocalization? Cell Cycle 1, 394–400 (2002).
Motti, M. L., De Marco, C., Califano, D., Fusco, A. & Viglietto, G. Akt-dependent T198 phosphorylation of cyclin-dependent kinase inhibitor p27kip1 in breast cancer. Cell Cycle 3, e89–e95 (2004).
Psyrri, A. et al. Subcellular localization and protein levels of cyclin-dependent kinase inhibitor p27 independently predict for survival in epithelial ovarian cancer. Clin. Cancer Res. 11, 8384–8390 (2005).
Baldassarre, G. et al. p27Kip1-stathmin interaction influences sarcoma cell migration and invasion. Cancer Cell 7, 51–63 (2005).
McAllister, S. S., Becker-Hapak, M., Pintucci, G., Pagano, M. & Dowdy, S. F. Novel p27kip1 C-terminal scatter domain mediates Rac-dependent cell migration independent of cell cycle arrest functions. Mol. Cell Biol. 23, 216–228 (2003).
Wu, F. Y. et al. Reduction of cytosolic p27Kip1 inhibits cancer cell motility, survival, and tumorigenicity. Cancer Res. 66, 2162–2172 (2006).
Denicourt, C., Saenz, C. C., Datnow, B., Cui, X. S. & Dowdy, S. F. Relocalized p27KiP1 tumor suppressor functions as a cytoplasmic metastatic oncogene in melanoma. Cancer Res. 67, 9238–9243 (2007).
Besson, A. et al. Discovery of an oncogenic activity in p27Kip1 that causes stem cell expansion and a multiple tumor phenotype. Genes Dev. 21, 1731–1746 (2007). Identified a novel pro-oncogenic action of p27 to promote expansion of cells with self-renewal capacity or tumour-initiating function.
Jordan, R., Bradley, G. & Slingerland, J. M. Reduced levels of the cell-cycle inhibitor p27KIP1 in epithelial dysplasia and carcinoma of the oral cavity. Am. J. Pathol. 152, 1–6 (1998).
De Paola, F. et al. p27/kip1 expression in normal epithelium, benign and neoplastic breast lesions. J. Pathol. 196, 26–31 (2002).
Moriya, T. et al. Immunohistochemical analysis of Ki-67, p53, p21, and p27 in benign and malignant apocrine lesions of the breast: its correlation to histologic findings in 43 cases. Mod. Pathol. 13, 13–18 (2000).
Oh, Y. L. et al. Expression of p21Waf1, p27Kip1 and cyclin D1 proteins in breast ductal carcinoma in situ: Relation with clinicopathologic characteristics and with p53 expression and estrogen receptor status. Path. Int. 51, 94–99 (2001).
Han, S. et al. Reduced expression of p27Kip1 protein is associated with poor clinical outcome of breast cancer patients treated with systemic chemotherapy and is linked to cell proliferation and differentiation. Breast Cancer Res. Treat. 55, 161–167 (1999).
Massarelli, E. et al. Loss of E-cadherin and p27 expression is associated with head and neck squamous tumorigenesis. Cancer 103, 952–959 (2005).
Pruneri, G. et al. Clinical relevance of expression of the CIP/KIP cell-cycle inhibitors p21 and p27 in laryngeal cancer. J. Clin. Oncol. 17, 3150–3159 (1999).
Vis, A. N. et al. Prognostic value of cell cycle proteins p27kip1 and MIB-1, and the cell adhesion protein CD44s in surgically treated patients with prostate cancer. J. Urol. 164, 2156–2161 (2000).
Cordon-Cardo, C. et al. Distinct altered patterns of p27KIP1 gene expression in benign prostatic hyperplasia and prostatic carcinoma. J. Natl Cancer Inst. 90, 1284–1291 (1998).
Tsihlias, J. et al. Loss of cyclin-dependent kinase inhibitor p27Kip1 is a novel prognostic factor in localized human prostate adenocarcinoma. Cancer Res. 58, 542–548 (1998).
Sui, L. et al. Implication of malignancy and prognosis of p27Kip1, Cyclin E, and Cdk2 expression in epithelial ovarian tumors. Gynecol. Oncol. 83, 56–63 (2001).
Korkolopoulou, P. et al. The combined evaluation of p27Kip1 and Ki-67 expression provides independent information on overall survival of ovarian carcinoma patients. Gynecol. Oncol. 85, 404–414 (2002).
Yatabe, Y. et al. p27Kip1 in human lung cancers: differential changes in small cell and non-small cell carcinomas. Cancer Res. 58, 1042–1047 (1998).
Ishihara, S. et al. The cyclin-dependent kinase inhibitor p27 as a prognostic factor in advanced non-small cell lung cancer: its immunohistochemical evaluation using biopsy specimens. Lung Cancer 26, 187–194 (1999).
Hommura, F. et al. Prognostic significance of p27KIP1 protein and ki-67 growth fraction in non-small cell lung cancers. Clin. Cancer Res. 6, 4073–4081 (2000).
Tsukamoto, S. et al. Reduced expression of cell-cycle regulator p27Kip1 correlates with a shortened survival in non-small cell lung cancer. Lung Cancer 34, 83–90 (2001).
Hayashi, H. et al. High cyclin E and low p27/Kip1 expressions are potentially poor prognostic factors in lung adenocarcinoma patients. Lung Cancer 34, 59–65 (2001).
Hirabayashi, H. et al. Prognostic significance of p27KIP1 expression in resected non-small cell lung cancers: analysis in combination with expressions of p16INK4A, pRB, and p53. J. Surg. Oncol. 81, 177–184 (2002).
Takahashi, S. et al. Relationship between postoperative recurrence and expression of cyclin E, p27, and Ki-67 in non-small cell lung cancer without lymph node metastases. Int. J. Clin. Oncol. 7, 349–355 (2002).
Catzavelos, C. et al. Reduced expression of the cell cycle inhibitor p27Kip1 in non-small cell lung carcinoma: a potential prognostic factor independent of ras. Cancer Res. 59, 684–688 (1999).
Esposito, V. et al. Prognostic role of the cyclin-dependent kinase inhibitor p27 in non-small cell lung cancer. Cancer Res. 57, 3381–3385 (1997).
Hirsch, F. R. et al. Epidermal growth factor receptor in non-small-cell lung carcinomas: Correlation between gene copy number and protein expression and impact on prognosis. J. Clin. Oncol. 21, 3798–3807 (2003).
Lynch, T. J. et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 350, 2129–2139 (2004).
Amann, J. et al. Aberrant epidermal growth factor receptor signaling and enhanced sensitivity to EGFR inhibitors in lung cancer. Cancer Res. 65, 226–235 (2005).
Anayama, T., Furihata, M., Ishikawa, T., Ohtsuki, Y. & Ogoshi, S. Positive correlation between p27Kip1 expression and progression of human esophageal squamous cell carcinoma. Int. J. Cancer 79, 439–443 (1998).
Fan, G. K. et al. Expression of protein p27 is associated with progression and prognosis in laryngeal cancer. Laryngoscope 109, 815–820 (1999).
Itami, A., Shimada, Y., Watanabe, G. & Imamura, M. Prognostic value of p27Kip1 and CyclinD1 expression in esophageal cancer. Oncology 57, 311–317 (1999).
Mineta, H. et al. Low p27 expression correlates with poor prognosis for patients with oral tongue squamous cell carcinoma. Cancer 85, 1011–1017 (1999).
Fujieda, S. et al. Expression of p27 is associated with Bax expression and spontaneous apoptosis in oral and oropharyngeal carcinoma. Int. J. Cancer 84, 315–320 (1999).
Venkatesan, T. K. et al. Prognostic significance of p27 expression in carcinoma of the oral cavity and oropharynx. Laryngoscope 109, 1329–1333 (1999).
Shamma, A. et al. Loss of p27KIP1 expression predicts poor prognosis in patients with esophageal squamous cell carcinoma. Oncology 58, 152–158 (2000).
Kagawa, Y., Yoshida, K., Hirai, T. & Toge, T. Significance of the expression of p27Kip1 in esophageal squamous cell carcinomas. Dis. Esophagus. 13, 179–184 (2000).
Tamura, N. et al. Cyclin-dependent kinase inhibitor p27 is related to cell proliferation and prognosis in laryngeal squamous cell carcinomas. J. Laryngol. Otol. 115, 400–406 (2001).
Kuo, M. Y. et al. Prognostic role of p27Kip1 expression in oral squamous cell carcinoma in Taiwan. Oral Oncol. 38, 172–178 (2002).
Korkmaz, H. et al. Prognostic significance of G1 cell-cycle inhibitors in early laryngeal cancer. Am. J. Otolaryngol. 26, 77–82 (2005).
Langer, R. et al. Prognostic significance of expression patterns of c-erbB-2, p53, p16INK4A, p27KIP1, cyclin D1 and epidermal growth factor receptor in oesophageal adenocarcinoma: a tissue microarray study. J. Clin. Pathol. 59, 631–634 (2006).
Loda, M. et al. Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas. Nature Med. 3, 231–234 (1997). Among the first studies to show loss of p27 protein expression is prognostic in human cancer. Showed that lysates from colon cancers with low p27 levels exhibit proteolytic activity toward recombinant p27 in vitro.
Belluco, C. et al. Absence of the cell cycle inhibitor p27Kip1 protein predicts poor outcome in patients with stage I–III colorectal cancer. Ann. Surg. Oncol. 6, 19–25 (1999).
Palmqvist, R., Stenling, R., Oberg, A. & Landberg, G. Prognostic significance of p27Kip1 expression in colorectal cancer: a clinico-pathological characterization. J. Pathol. 188, 18–23 (1999).
Tenjo, T. et al. Prognostic significance of p27kip1 protein expression and spontaneous apoptosis in patients with colorectal adenocarcinomas. Oncology 58, 45–51 (2000).
Rossi, H. A. et al. The prognostic value of invariant chain (Ii) and her-2/neu expression in curatively resected colorectal cancer. Cancer J. 8, 268–275 (2002).
Noguchi, T. et al. Prognostic significance of p27/kip1 and apoptosis in patients with colorectal carcinoma. Oncol. Rep. 10, 827–831 (2003).
Galizia, G. et al. Determination of molecular marker expression can predict clinical outcome in colon carcinomas. Clin. Cancer Res. 10, 3490–3499 (2004).
Manne, U. et al. Prognostic significance of p27(kip-1) expression in colorectal adenocarcinomas is associated with tumor stage. Clin. Cancer Res. 10, 1743–1752 (2004).
Rosati, G., Chiacchio, R., Reggiardo, G., De Sanctis, D. & Manzione, L. Thymidylate synthase expression, p53, bcl-2, Ki-67 and p27 in colorectal cancer: relationships with tumor recurrence and survival. Tumour Biol. 25, 258–263 (2004).
Wu, J. T. et al. Prognostic significance of DCC and p27Kip1 in colorectal cancer. Appl. Immunohistochem. Mol. Morphol. 13, 45–54 (2005).
Watson, N. F. et al. Cytoplasmic expression of p27kip1 is associated with a favourable prognosis in colorectal cancer patients. World J. Gastroenterol. 12, 6299–6304 (2006).
Sarli, L. et al. Loss of p27 expression and microsatellite instability in sporadic colorectal cancer. Surg. Oncol. 15, 97–106 (2006).
Ciaparrone, M. et al. Localization and expression of p27KIP1 in multistage colorectal carcinogenesis. Cancer Res. 58, 114–122 (1998).
Cheng, J. D., Werness, B. A., Babb, J. S. & Meropol, N. J. Paradoxical correlations of cyclin-dependent kinase inhibitors p21waf1/cip1 and p27kip1 in metastatic colorectal carcinoma. Clin. Cancer Res. 5, 1057–1062 (1999).
Galizia, G. et al. Prognostic value of p27, p53, and vascular endothelial growth factor in Dukes A and B colon cancer patients undergoing potentially curative surgery. Dis. Colon Rectum 47, 1904–1914 (2004).
Yang, R. M. et al. Low p27 expression predicts poor disease-free survival in patients with prostate cancer. J. Urol. 159, 941–945 (1998).
Cote, R. J. et al. Association of p27Kip1 levels with recurrence and survival in patients with stage C prostate carcinoma. J. Natl Cancer Inst. 90, 916–920 (1998).
Freedland, S. J. et al. Preoperative p27 status is an independent predictor of prostate specific antigen failure following radical prostatectomy. J. Urol. 169, 1325–1330 (2003).
Li, R. et al. Biological correlates of p27 compartmental expression in prostate cancer. J. Urol. 175, 528–532 (2006).
Kuczyk, M. A. et al. Predictive value of altered p27Kip1 and p21WAF/Cip1 protein expression for the clinical prognosis of patients with localized prostate cancer. Oncol. Rep. 8, 1401–1407 (2001).
Cheville, J. C. et al. Expression of p27kip1 in prostatic adenocarcinoma. Mod. Pathol. 11, 324–328 (1998).
Thomas, G. V. et al. Preoperative prostate needle biopsy p27 correlates with subsequent radical prostatectomy p27, Gleason grade and pathological stage. J. Urol. 164, 1987–1991 (2000).
Freedland, S. J. et al. Predicting biochemical recurrence after radical prostatectomy for patients with organ-confined disease using p27 expression. Urology 61, 1187–1192 (2003).
Newcomb, E. W. et al. Expression of the cell cycle inhibitor p27KIP1 is a new prognostic marker associated with survival in epithelial ovarian tumors. Am. J. Pathol. 154, 119–125 (1999).
Baekelandt, M., Holm, R., Trope, C. G., Nesland, J. M. & Kristensen, G. B. Lack of independent prognostic significance of p21 and p27 expression in advanced ovarian cancer: an immunohistochemical study. Clin. Cancer Res. 5, 2848–2853 (1999).
Masciullo, V. et al. p27Kip1 expression is associated with clinical outcome in advanced epithelial ovarian cancer: multivariate analysis. Clin. Cancer Res. 6, 4816–4822 (2000).
Schmider-Ross, A. et al. Cyclin-dependant kinase inhibitors CIP1 (p21) and KIP1 (p27) in ovarian cancer. J. Cancer Res. Clin. Oncol. 132, 163–170 (2006).
Barnes, A. et al. Expression of p27kip I in breast cancer and its prognostic significance. J. Pathology 201, 451–459 (2003).
Gillett, C. E., Smith, P., Peters, G., Lu, X. & Barnes, D. M. Cyclin-dependent kinase inhibitor p27Kip1 expression and interaction with other cell cycle-associated proteins in mammary carcinoma. J. Pathol. 187, 200–206 (1999).
Barbareschi, M. et al. p27kip1 expression in breast carcinomas: an immunohistochemical study on 512 patients with long-term follow-up. Int. J. Cancer 89, 236–241 (2000).
Leivonen, M., Nordling, S., Lundin, J., von Boguslawski, K. & Haglund, C. p27 expression correlates with short-term, but not with long-term prognosis in breast cancer. Breast Cancer Res. Treat. 67, 15–22 (2001).
Han, S. et al. Prognostic implication of cyclin E expression and its relationship with cyclin D1 and p27Kip1 expression on tissue microarrays of node negative breast cancer. J. Surg. Oncol. 83, 241–247 (2003).
Porter, P. L. et al. p27Kip1 and cyclin E expression and breast cancer survival after treatment with adjuvant chemotherapy. J. Natl Cancer Inst. 98, 1723–1731 (2006). An important paper confirming the prognostic potential of p27 and shows that p27 loss is most prognostic in ER-positive human breast cancers in retrospective analysis of samples from a prospective randomized clinical trial.
Wu, J. et al. Prognostic role of p27Kip1 and apoptosis in human breast cancer. Br. J. Cancer 79, 1572–1578 (1999).
Tsuchiya, A., Zhang, G. J. & Kanno, M. Prognostic impact of cyclin-dependent kinase inhibitor p27kip1 in node-positive breast cancer. J. Surg. Oncol. 70, 230–234 (1999).
Chappuis, P. O. et al. Germline BRCA1/2 mutations and p27Kip1 protein levels independently predict outcome after breast cancer. J. Clin. Oncol. 18, 4045–4052 (2000).
Nohara, T., Ryo, T., Iwamoto, S., Gon, G. & Tanigawa, N. Expression of cell-cycle regulator p27 is correlated to the prognosis and ER expression in breast carcinoma patients. Oncology 60, 94–100 (2001).
Pohl, G. et al. High p27Kip1 expression predicts superior relapse-free and overall survival for premenopausal women with early-stage breast cancer receiving adjuvant treatment with tamoxifen plus goserelin. J. Clin. Oncol. 21, 3594–3600 (2003). The first study showing the predictive potential of p27 in a prospective trial. This important study showed that reduced p27 levels correlate with poor outcome in multivariate analysis and reduced response to endocrine therapy in pre-menopausal women with breast cancer in a retrospective analysis of p27 in samples collected in a prospective clinical trial.
Foulkes, W. D. et al. The prognostic implication of the basal-like (cyclin E high/p27 low/p53+/glomeruloid-microvascular-proliferation+) phenotype of BRCA1-related breast cancer. Cancer Res. 64, 830–835 (2004).
Reed, W., Florems, V. A., Holm, R., Hannisdal, E. & Nesland, J. M. Elevated levels of p27, p21 and cyclin D1 correlate with positive oestrogen and progesterone receptor status in node-negative breast carcinoma patients. Virchows Arch. 435, 116–124 (1999).
Slamon, D. J. et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344, 783–792 (2001).
Osborne, C. K. Steroid hormone receptors in breast cancer management. Breast Cancer Res. Treat. 51, 227–238 (1998).
Oka, K., Suzuki, Y. & Nakano, T. Expression of p27 and p53 in cervical squamous cell carcinoma patients treated with radiotherapy alone: radiotherapeutic effect and prognosis. Cancer 88, 2766–2773 (2000).
Cariou, S. et al. Down-regulation of p21WAF1/CIP1 or p27Kip1 abrogates antiestrogen-mediated cell cycle arrest in human breast cancer cells. Proc. Natl Acad. Sci. USA 97, 9042–9046 (2000). This paper demonstrated that p27 and p21 are required for growth arrest by tamoxifen and other antioestrogens in breast cancer cells in culture.
Lane, H. A. et al. ErbB2 potentiates breast tumor proliferation through modulation of p27Kip1–CDK2 complex formation: receptor overexpression does not determine growth dependency. Mol. Cell Biol. 20, 3210–3223 (2000).
Hayes, D. F. Prognostic and predictive factors for breast cancer: translating technology to oncology. J. Clin. Oncol. 23, 1596–1597 (2005).
Van't Veer, L. J., Paik, S. & Hayes, D. F. Gene expression profiling of breast cancer: a new tumor marker. J. Clin. Oncol. 23, 1631–1635 (2005).
Oshita, F. et al. Increased expression levels of cyclin-dependent kinase inhibitor p27 correlate with good responses to platinum-based chemotherapy in non-small cell lung cancer. Oncol. Rep. 7, 491–495 (2000).
Kobayashi, M., Shiraishi, T., Tonouchi, H., Miki, C. & Kusunoki, M. 5-FU improves p27-related poor prognosis in patients with Astler-Coller B2-C colorectal carcinoma. Oncol. Rep. 9, 29–33 (2002).
Prall, F., Ostwald, C., Nizze, H. & Barten, M. Expression profiling of colorectal carcinomas using tissue microarrays: cell cycle regulatory proteins p21, p27, and p53 as immunohistochemical prognostic markers in univariate and multivariate analysis. Appl. Immunohistochem. Mol. Morphol. 12, 111–121 (2004).
Singh, S. P. et al. Loss or altered subcellular localization of p27 in Barrett's associated adenocarcinoma. Cancer Res. 58, 1730–1735 (1998).
Zeng, W. Q. et al. Relationships between levels of Skp2 and p27 in breast carcinomas and possible role of Skp2 as targeted therapy. Steroids 70, 770–774 (2005).
Chang, J. et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy J. Natl Cancer Inst. (in the press).
Hattori, T. et al. Pirh2 promotes ubiquitin-dependent degradation of the cyclin-dependent kinase inhibitor p27Kip1. Cancer Res. 67, 10789–10795 (2007).
Hauck, L. et al. Protein kinase CK2 links extracellular growth factor signaling with the control of p27Kip1 stability in the heart. Nature Med. 14, 315–324 (2008).
Acknowledgements
This work was supported by National Cancer Institute grant 1R01CA105118-01 to J.M.S. and by Austrian Science Fund (FWF, Projects P-18873 and Special Research Program “Cell Proliferation and Cell Death in Tumours” Grant SFB021) to L.H. J.M.S. is supported by the Braman Family Breast Cancer Institute of the University of Miami Sylvester Comprehensive Cancer Center. The authors apologize for omissions in citation and coverage. Strict space and citation limits preculde inclusion of many important past and recent works. We thank A. Farooq for help with generating figure 2.
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Glossary
- Multivariate analysis
-
The observation and analysis of more than one statistical variable at a time.
- Univariate analysis
-
The observation and analysis of one statistical variable at a time.
- Ki67
-
A monoclonal antibody that marks the late S phase of the cell cycle. This is frequently used to mark proliferating cells in tissues or cell suspensions.
- Gleason grading system
-
The 'gold standard' for grading prostate cancer, used by pathologists worldwide. This system involves assessing both the predominant and secondary pattern of gland formation within a prostate sample. The sample is scored to create a Gleason 'sum', ranging from 2 to 10, with the highest number indicating the most aggressive cancer. Patients with a Gleason sum of less than 6 typically respond well to therapy, whereas patients with a Gleason sum greater than 7 usually have poor outcomes.
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Chu, I., Hengst, L. & Slingerland, J. The Cdk inhibitor p27 in human cancer: prognostic potential and relevance to anticancer therapy. Nat Rev Cancer 8, 253–267 (2008). https://doi.org/10.1038/nrc2347
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DOI: https://doi.org/10.1038/nrc2347
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