Abstract
We recently discovered that stathmin was overexpressed in a subgroup of human breast carcinomas. Stathmin is a cytosolic phosphoprotein proposed to act as a relay integrating diverse cell signalling pathways, notably during the control of cell growth and differentiation. It may also be considered as one of the key regulators of cell division for its ability to destabilize microtubules in a phosphorylation-dependent manner. To assess the significance of stathmin overexpression in breast cancer, we evaluated the correlation of stathmin expression, quantified by reverse transcription polymerase chain reaction, with several disease parameters in a large series of human primary breast cancer (n = 133), obtained in strictly followed up women, whose clinico-pathological data were fully available. In agreement with our preliminary survey, stathmin was found overexpressed in a subgroup of tumours (22%). In addition, overexpression was correlated to the loss of steroid receptors (oestrogen, P = 0.0006; progesterone, P = 0.008), and to the Scarff–Bloom–Richardson histopathological grade III (P = 0.002), this latter being ascribable to the mitotic index component (P = 0.02). Furthermore studies at the DNA level indicated that stathmin is overexpressed irrespective of its genomic status. Our findings raise important questions concerning the causes and consequences of stathmin overexpression, and the reasons of its inability to counteract cell proliferation in the overexpression group. © 2000 Cancer Research Campaign
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Balogh A, Mège RM and Sobel A (1996) Growth and cell density-dependent expression of stathmin in C2 myoblasts in culture. Exp Cell Res 224: 8–15
Bargou RC, Wagener C, Bommert K, Arnold W, Daniel PT, Mapara MY, Grinstein E, Royer HD and Dorken B (1996) Blocking the transcription factor E2F/DP by dominant-negative mutants in a normal breast epithelial cell line efficiently inhibits apoptosis and induces tumor growth in SCID mice. J Exp Med 183: 1205–1213
Belmont LD and Mitchison TJ (1996) Identification of a protein that interacts with tubulin dimers and increases the catastrophe rate of microtubules. Cell 84: 623–631
Beretta L, Boutterin MC and Sobel A (1988) Phosphorylation of intracellular proteins related to the multihormonal regulation of prolactin: comparison of normal anterior pituitary cells in culture with the tumor-derived GH cell lines. Endocrinology 122: 40–51
Beretta L, Boutterin MC, Drouva S and Sobel A (1989) Phosphorylation of a group of proteins related to the physiological, multihormonal regulations of the various cell types in the anterior pituitary gland. Endocrinology 125: 1358–1364
Bièche I, Lachkar S, Becette V, Cifuentes-Diaz C, Sobel A, Lidereau R and Curmi P (1998) Overexpression of the stathmin gene in a subset of human breast cancer. Br J Cancer 78: 701–709
Bièche I, Onody XP, Laurendeau I, Olivi M, Vidaud, Lidereau R and Vidaud M (1999) Real-time reverse transcription-PCR assay for future management of ERBB2-based clinical applications. Clin Chem 45: 1148–1156
Bloom HJG and Richardson WW (1957) Histological grading and prognosis in breast cancer. Br J Cancer 11: 359–377
Brattsand G, Roos G, Marklund U, Ueda H, Landberg G, Nanberg E, Sideras P and Gullberg M (1993) Quantitative analysis of the expression and regulation of an activation-regulated phosphoprotein (oncoprotein 18) in normal and neoplastic cells. Leukemia 7: 569–579
Brattsand G, Marklund U, Nylander K, Roos G and Gullberg M (1994) Cell-cycle-regulated phosphorylation of oncoprotein 18 on ser16, ser25, and ser38. Eur J Biochem 220: 359–368
Chneiweiss H, Cordier J and Sobel A (1992) Stathmin phosphorylation is regulated in striatal neurons by vasoactive intestinal peptide and monoamines via multiple intracellular pathways. J Neurochem 58: 282–289
Chomczynski P and Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162: 156–159
Cooper HL, McDuffie E and Braverman R (1989) Human peripheral lymphocyte growth regulation and response to phorbol esters is linked to synthesis and phosphorylation of the cytosolic protein, prosolin. J Immunol 143: 956–963
Curmi PA, Andersen SSL, Lachkar S, Gavet O, Karsenti E, Knossow M and Sobel A (1997) The stathmin tubulin interaction in vitro. J Biol Chem 272: 25029–25036
Di Paolo G, Antonsson B, Kassel D, Riederer BM and Grenningloh G (1997) Phosphorylation regulates the microtubule-destabilizing activity of stathmin and its interaction with tubulin. FEBS Lett 416: 149–152
Doye V, Boutterin MC and Sobel A (1990) Phosphorylation of stathmin and other proteins related to nerve growth factor-induced regulation of PC12 cells. J Biol Chem 265: 11650–11655
EORTC Breast Cooperative Group (1980) Revision of the standards for the assessment of hormone receptors in human breast cancer. Report of the second EORTC Workshop, held on 16–17 March 1979, in the Netherlands Cancer Institute. Eur J Cancer 16: 1513–1516
Foley KP, Leonard MW and Engel JD (1993) Quantitation of RNA using the polymerase chain reaction. TIG 9: 380–385
Friedrich B, Grönberg H, Landström M, Bergh A and Gullberg M (1995) Differentiation-stage specific expression of oncoprotein 18 in human and rat prostatic adenocarcinoma. Prostate 27: 102–109
Gavet O, Ozon S, Manceau V, Lawler S, Curmi P and Sobel A (1998) The stathmin phosphoprotein family: intracellular localization and effects on the microtubule network. J Cell Sci 111: 3333–3346
Ghosh PK, Anderson NG, Cohen P, Taketo M, Atweh GF and Lebowitz P (1993) Expression of the leukemia-associated gene p18 in normal and malignant tissues: inactivation of expression in a patient with cleaved B-cell lymphoma/leukemia. Oncogene 8: 2869–2872
Hailat N, Strahler JR, Melhem RF, Zhu XX, Brodeur G, Seeger RC, Reynolds CP and Hanash SM (1990) N-myc gene amplification in neuroblastoma is associated with altered phosphorylation of a proliferation related polypeptide (Op 18). Oncogene 5: 1615–1618
Han I and Kudlow JE (1997) Reduced O glycosylation of Sp1 is associated with increased proteasome susceptibility. Mol Cell Biol 17: 2550–2558
Hanash SM, Strahler JR, Kuick R, Chu EHY and Nichols D (1988) Identification of a polypeptide associated with the malignant phenotype in the acute leukemia. J Biol Chem 263: 12813–12815
Horwitz SB, Shen H-J, He L, Dittmar P, Neef R, Chen J and Schubart UK (1997) The microtubule-destabilizing activity of metablastin (p19) is controlled by phosphorylation. J Biol Chem 272: 8129–8132
Hunt KK, Deng J, Liu TJ, Wilson-Heiner M, Swisher SG, Clayman G and Hung MC (1997) Adenovirus-mediated overexpression of the transcription factor E2F-1 induces apoptosis in human breast and ovarian carcinoma cell lines and does not require p53. Cancer Res 57: 4722–4726
Jensen SJ, Sulman EP, Maris JM, Matise TC, Vojta PJ, Barrett JC, Brodeur GM and White PS (1997) An integrated transcript map of human chromosome 1p35–p36. Genomics 42: 126–136
Jourdain L, Curmi P, Sobel A, Pantaloni D and Carlier MF (1997) Stathmin: a tubulin-sequestering protein which forms a ternary T2S complex with two tubulin molecules. Biochemistry 36: 10817–10821
Kadonaga JT, Carner KR, Masiarz FR and Tjian R (1997) Isolation of cDNA encoding transcription factor Sp1 and functional analysis of the DNA binding domain. Cell 51: 1079–1090
Kaplan EL and Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457–481
Koppel J, Loyer P, Maucuer A, Rehák P, Manceau V, Guguen-Guillouzo C and Sobel A (1993) Induction of stathmin expression during liver regeneration. FEBS Lett 331: 65–70
Larsson N, Melander H, Marklund U, Osterman O and Gullberg M (1995) G2/M transition requires multisite phosphorylation of oncoprotein 18 by two distinct protein kinase systems. J Biol Chem 270: 14175–14183
Larsson N, Marklund U, Gradin HM, Brattsand G and Gullberg M (1997) Control of microtubule dynamics by oncoprotein 18: dissection of the regulatory role of multisite phosphorylation during mitosis. Mol Cell Biol 17: 5530–5539
Lawler S, Gavet O, Rich T and Sobel A (1998) Stathmin overexpression in 293 cells affects signal transduction and the cell cycle. FEBS Lett 421: 55–60
Lazar V, Diez SG, Laurent A, Giovangrandi Y, Radvanyi F, Chopin D, Bidart JM, Bellet D and Vidaud M (1995) Expression of human chorionic gonadotropin beta subunit genes in superficial and invasive bladder carcinomas. Cancer Res 55: 3735–3738
Luo X-N, Mookerjee B, Ferrari A, Mistry S and Atweh GF (1994) Regulation of phosphoprotein p18 in leukemic cells. Cell cycle regulated phosphorylation by p34cdc2kinase. J Biol Chem 269: 10312–10318
Marklund U, Osterman O, Melander H, Bergh A and Gullberg M (1994) The phenotype of a ‘cdc2 kinase target site-deficient’ mutant of oncoprotein 18 reveals a role of this protein in cell cycle control. J Biol Chem 269: 30626–30635
Marklund U, Larsson N, Melander Gradin H, Brattsand G and Gullberg M (1996) Oncoprotein 18 is a phosphorylation-responsive regulator of microtubule dynamics. EMBO J 15: 5290–5298
Maucuer A, Camonis JH and Sobel A (1995) Stathmin interaction with a novel putative kinase and coiled-coil forming protein domains. Proc Natl Acad Sci USA 92: 3100–3104
Maucuer A, Ozon S, Manceau V, Gavet O, Lawler S, Curmi P and Sobel A (1997) KIS is a protein kinase with an RNA recognition motif. J Biol Chem 272: 23151–23156
Melander Gradin H, Marklund U, Larsson N, Chatila TA and Gullberg M (1997) Regulation of microtubule dynamics by Ca2+calmodulin-dependent kinase IV/Gr-dependent phosphorylation of oncoprotein 18. Mol Cell Biol 17: 3459–3467
Melander Gradin H, Larsson N, Marklund U and Gullberg M (1998) Regulation of microtubule dynamics by extracellular signals: cAMP-dependent protein kinase switches off the activity of Oncoprotein 18 in intact cells. J Cell Biol 140: 1–11
Melhem RF, Zhu XX, Hailat N, Strahler JR and Hanash SM (1991) Characterization of the gene for a proliferation-related phosphoprotein (oncoprotein 18) expressed in high amounts in acute leukemia. J Biol Chem 266: 17747–17753
Nylander K, Marklund U, Brattsand G, Gullberg M and Roos G (1995) Immunohistochemical detection of oncoprotein 18 (Op18) in malignant lymphomas. Histochemical Journal 27: 155–160
Pannetier C, Delassus S, Darche S, Saucier C and Kourilsky P (1993) Quantitative titration of nucleic acids by enzymatic amplification reactions run to saturation. Nucl Acid Res 21: 577–583
Pasmantier R, Danoff A, Fleischer N and Schubart UK (1986) P19, a hormonally regulated phosphoprotein of peptide-hormone producing cells: secretagogue-induced phosphorylation in AtT-20 mouse pituitary tumor cells and in rat and hamster insulinoma cells. Endocrinology 19: 1229–1238
Peto R, Pike MC, Armitage P, Breslow NE, Cox DR Howard SV, Mantel N, McPherson K, Peto J and Smith PG (1977) Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. Analysis and examples. Br J Cancer 35: 1–39
Peyron J-F, Aussel C, Ferrua B, Häring H and Fehlmann M (1989) Phosphorylation of two cytosolic proteins. An early event of T-cell activation. Biochem J 258: 505–510
Pugh BF and Tjian R (1990) Mechanism of transcriptional activation by Sp1: evidence for coactivators. Cell 61: 1187–1197
Pugh BF and Tjian R (1991) Transcription from a TATA-less promoter requires a multisubunit TFIID complex. Genes Dev 5: 1935–1945
Sambrook J, Fritsch EF and Maniatis T (1989). Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press: Cold Spring Harbor, NY
Sarkar G and Bolander ME (1994) The ‘looped oligo’ method for generating reference molecules for quantitative PCR. BioTechniques 17: 864–866
Schubart UK, Xu J, Fan W, Cheng G Goldstein H, Alpini G, Shafritz DA, Amat JA, Farook M, Norton WT, Owen TA, Lian JB and Stein GS (1992) Widespread differentiation stage-specific expression of the gene encoding phosphoprotein p19 (metablastin) in mammalian cells. Differentiation 51: 21–32
Slamon DJ, Goldophin W, Jones LA, Holt JA, Wong SG, Keith DE, Levin WJ, Stuart SG, Udove J and Ullrich A (1989) Studies of HER-2/neu protooncogene in human breast and ovarian cancer. Science 244: 707–712
Sobel A (1991) Stathmin: a relay phosphoprotein for multiple signal transduction?. Trends Biochem Sci 16: 301–305
Sobel A and Tashjian AH, Jr (1983) Distinct patterns of cytoplasmic protein phosphorylation related to regulation of synthesis and release of prolactin by GH cells. J Biol Chem 258: 10312–10324
Sobel A, Boutterin MC, Beretta L, Chneiweiss H, Doye V and Peyro-Saint-Paul H (1989) Intracellular substrates for extracellular signaling: characterization of a ubiquitous, neuron-enriched phosphoprotein (Stathmin). J Biol Chem 264: 3765–3772
Strahler JR, Lamb BJ, Ungar DR, Fox DA and Hanash SM (1992) Cell cycle progression is associated with distinct patterns of phosphorylation of Op18. Biochem Biophys Res Commun 185: 197–203
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Curmi, P., Noguès, C., Lachkar, S. et al. Overexpression of stathmin in breast carcinomas points out to highly proliferative tumours. Br J Cancer 82, 142–150 (2000). https://doi.org/10.1054/bjoc.1999.0891
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1054/bjoc.1999.0891
Keywords
This article is cited by
-
Differential proteomics reveals overexpression of ferroptosis-related proteins in cervical cancer tissue
Journal of Proteins and Proteomics (2023)
-
HMGA1 positively regulates the microtubule-destabilizing protein stathmin promoting motility in TNBC cells and decreasing tumour sensitivity to paclitaxel
Cell Death & Disease (2022)
-
Newly identified breast luminal progenitor and gestational stem cell populations likely give rise to HER2-overexpressing and basal-like breast cancers
Discover Oncology (2022)
-
Differences in DNA methylation profiles by histologic subtype of paediatric germ cell tumours: a report from the Children’s Oncology Group
British Journal of Cancer (2018)
-
Downregulation of stathmin 1 in human gallbladder carcinoma inhibits tumor growth in vitro and in vivo
Scientific Reports (2016)
