Stathmin is a prognostic marker in many cancers, including endometrial cancer. Preclinical studies, predominantly in breast cancer, have suggested that stathmin may additionally be a predictive marker for response to paclitaxel. We first evaluated the response to paclitaxel in endometrial cancer cell lines before and after stathmin knock-down. Subsequently we investigated the clinical response to paclitaxel containing chemotherapy in metastatic endometrial cancer in relation to stathmin protein level in tumors. Stathmin level was also determined in metastatic lesions, analyzing changes in biomarker status on disease progression. Knock-down of stathmin improved sensitivity to paclitaxel in endometrial carcinoma cell lines with both naturally higher and lower sensitivity to paclitaxel. In clinical samples, high stathmin level was demonstrated to be associated with poor response to paclitaxel containing chemotherapy and to reduced disease specific survival only in patients treated with such combination. Stathmin level increased significantly from primary to metastatic lesions. This study suggests, supported by both preclinical and clinical data, that stathmin could be a predictive biomarker for response to paclitaxel treatment in endometrial cancer. Re-assessment of stathmin level in metastatic lesions prior to treatment start may be relevant. Also, validation in a randomized clinical trial will be important.
References
[1]
Belletti B, Baldassarre G (2011) Stathmin: a protein with many tasks. New biomarker and potential target in cancer. Expert opinion on therapeutic targets 15: 1249–1266. doi: 10.1517/14728222.2011.620951
[2]
Marklund U, Larsson N, Gradin HM, Brattsand G, Gullberg M (1996) Oncoprotein 18 is a phosphorylation-responsive regulator of microtubule dynamics. The EMBO journal 15: 5290–5298.
[3]
Mistry SJ, Li HC, Atweh GF (1998) Role for protein phosphatases in the cell-cycle-regulated phosphorylation of stathmin. The Biochemical journal 334 (Pt 1): 23–29.
[4]
Rubin CI, Atweh GF (2004) The role of stathmin in the regulation of the cell cycle. Journal of cellular biochemistry 93: 242–250. doi: 10.1002/jcb.20187
[5]
Biomarkers Definitions Working G (2001) Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clinical pharmacology and therapeutics 69: 89–95.
[6]
Baquero MT, Hanna JA, Neumeister V, Cheng H, Molinaro AM, et al. (2012) Stathmin expression and its relationship to microtubule-associated protein tau and outcome in breast cancer. Cancer 118: 4660–4669. doi: 10.1002/cncr.27453
[7]
Bieche I, Lachkar S, Becette V, Cifuentes-Diaz C, Sobel A, et al. (1998) Overexpression of the stathmin gene in a subset of human breast cancer. British journal of cancer 78: 701–709.
[8]
Jeon TY, Han ME, Lee YW, Lee YS, Kim GH, et al. (2010) Overexpression of stathmin1 in the diffuse type of gastric cancer and its roles in proliferation and migration of gastric cancer cells. British journal of cancer 102: 710–718.
[9]
Kang W, Tong JH, Chan AW, Lung RW, Chau SL, et al. (2012) Stathmin1 plays oncogenic role and is a target of microRNA-223 in gastric cancer. PLoS One 7: e33919. doi: 10.1371/journal.pone.0033919
[10]
Kouzu Y, Uzawa K, Koike H, Saito K, Nakashima D, et al. (2006) Overexpression of stathmin in oral squamous-cell carcinoma: correlation with tumour progression and poor prognosis. British journal of cancer 94: 717–723.
[11]
Liu F, Sun YL, Xu Y, Liu F, Wang LS, et al. (2013) Expression and phosphorylation of stathmin correlate with cell migration in esophageal squamous cell carcinoma. Oncology reports 29: 419–424. doi: 10.3892/or.2012.2157
[12]
Salvesen HB, Carter SL, Mannelqvist M, Dutt A, Getz G, et al. (2009) Integrated genomic profiling of endometrial carcinoma associates aggressive tumors with indicators of PI3 kinase activation. Proceedings of the National Academy of Sciences of the United States of America 106: 4834–4839. doi: 10.1073/pnas.0806514106
[13]
Su D, Smith SM, Preti M, Schwartz P, Rutherford TJ, et al. (2009) Stathmin and tubulin expression and survival of ovarian cancer patients receiving platinum treatment with and without paclitaxel. Cancer 115: 2453–2463. doi: 10.1002/cncr.24282
[14]
Trovik J, Mauland KK, Werner HM, Wik E, Helland H, et al. (2012) Improved survival related to changes in endometrial cancer treatment, a 30-year population based perspective. Gynecol Oncol 125: 381–387. doi: 10.1016/j.ygyno.2012.01.050
[15]
Trovik J, Wik E, Stefansson IM, Marcickiewicz J, Tingulstad S, et al. (2011) Stathmin overexpression identifies high-risk patients and lymph node metastasis in endometrial cancer. Clin Cancer Res 17: 3368–3377. doi: 10.1158/1078-0432.ccr-10-2412
[16]
Saal LH, Johansson P, Holm K, Gruvberger-Saal SK, She QB, et al. (2007) Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity. Proceedings of the National Academy of Sciences of the United States of America 104: 7564–7569. doi: 10.1073/pnas.0702507104
[17]
Salvesen HB, Haldorsen IS, Trovik J (2012) Markers for individualised therapy in endometrial carcinoma. The lancet oncology 13: e353–361. doi: 10.1016/s1470-2045(12)70213-9
[18]
La Thangue NB, Kerr DJ (2011) Predictive biomarkers: a paradigm shift towards personalized cancer medicine. Nature reviews Clinical oncology 8: 587–596. doi: 10.1038/nrclinonc.2011.121
[19]
Sawyers C (2004) Targeted cancer therapy. Nature 432: 294–297. doi: 10.1038/nature03095
[20]
Ong FS, Das K, Wang J, Vakil H, Kuo JZ, et al. (2012) Personalized medicine and pharmacogenetic biomarkers: progress in molecular oncology testing. Expert review of molecular diagnostics 12: 593–602. doi: 10.1586/erm.12.59
[21]
Shankaran V, Obel J, Benson AB 3rd (2010) Predicting response to EGFR inhibitors in metastatic colorectal cancer: current practice and future directions. The oncologist 15: 157–167. doi: 10.1634/theoncologist.2009-0221
[22]
Butrynski JE, D'Adamo DR, Hornick JL, Dal Cin P, Antonescu CR, et al. (2010) Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor. The New England journal of medicine 363: 1727–1733. doi: 10.1056/nejmoa1007056
[23]
Hudis CA (2007) Trastuzumab – mechanism of action and use in clinical practice. The New England journal of medicine 357: 39–51. doi: 10.1056/nejmra043186
[24]
Alli E, Bash-Babula J, Yang JM, Hait WN (2002) Effect of stathmin on the sensitivity to antimicrotubule drugs in human breast cancer. Cancer Res 62: 6864–6869.
[25]
Alli E, Yang JM, Ford JM, Hait WN (2007) Reversal of stathmin-mediated resistance to paclitaxel and vinblastine in human breast carcinoma cells. Molecular pharmacology 71: 1233–1240. doi: 10.1124/mol.106.029702
[26]
Carr JR, Park HJ, Wang Z, Kiefer MM, Raychaudhuri P (2010) FoxM1 mediates resistance to herceptin and paclitaxel. Cancer Res 70: 5054–5063. doi: 10.1158/0008-5472.can-10-0545
[27]
Mistry SJ, Atweh GF (2006) Therapeutic interactions between stathmin inhibition and chemotherapeutic agents in prostate cancer. Molecular cancer therapeutics 5: 3248–3257. doi: 10.1158/1535-7163.mct-06-0227
[28]
Mitra M, Kandalam M, Sundaram CS, Verma RS, Maheswari UK, et al. (2011) Reversal of stathmin-mediated microtubule destabilization sensitizes retinoblastoma cells to a low dose of antimicrotubule agents: a novel synergistic therapeutic intervention. Investigative ophthalmology & visual science 52: 5441–5448. doi: 10.1167/iovs.10-6973
[29]
Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA, et al. (2012) The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483: 603–607. doi: 10.1016/s0959-8049(12)70726-8
[30]
American Type Culture Collection Standards Development Organization Workgroup ASN (2010) Cell line misidentification: the beginning of the end. Nat Rev Cancer 10: 441–448.
[31]
Lacroix M (2008) Persistent use of “false” cell lines. International journal of cancer Journal international du cancer 122: 1–4. doi: 10.1002/ijc.23233
[32]
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, et al. (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). European journal of cancer 45: 228–247. doi: 10.1016/j.ejca.2008.10.026
[33]
Kononen J, Bubendorf L, Kallioniemi A, Barlund M, Schraml P, et al. (1998) Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 4: 844–847. doi: 10.1038/nm0798-844
[34]
Engelsen IB, Stefansson IM, Akslen LA, Salvesen HB (2008) GATA3 expression in estrogen receptor alpha-negative endometrial carcinomas identifies aggressive tumors with high proliferation and poor patient survival. Am J Obstet Gynecol 199: 543 e541–547.
[35]
Salvesen HB, Das S, Akslen LA (2000) Loss of nuclear p16 protein expression is not associated with promoter methylation but defines a subgroup of aggressive endometrial carcinomas with poor prognosis. Clin Cancer Res 6: 153–159.
[36]
Paik D, Cocco E, Bellone S, Casagrande F, Bellone M, et al. (2010) Higher sensitivity to patupilone versus paclitaxel chemotherapy in primary uterine serous papillary carcinoma cell lines with high versus low HER-2/neu expression in vitro. Gynecol Oncol 119: 140–145. doi: 10.1016/j.ygyno.2010.06.024
[37]
Hiramatsu HP, Kikuchi Y, Seto H, Nagata I (2000) In vitro sensitivity of human endometrial cancer cell lines to paclitaxel or irinotecan (CPT-11) in combination with other aniticancer drugs. Anticancer Drugs 11: 573–578. doi: 10.1097/00001813-200008000-00009
[38]
Vandenput I, Trovik J, Leunen K, Wik E, Stefansson I, et al. (2011) Evolution in endometrial cancer: evidence from an immunohistochemical study. Int J Gynecol Cancer 21: 316–322. doi: 10.1097/igc.0b013e31820575f5
[39]
Amant F, Mirza MR, Creutzberg CL (2012) Cancer of the corpus uteri. Int J Gynaecol Obstet 119 Suppl 2S110–117. doi: 10.1016/s0020-7292(12)60024-1
[40]
Halle MK, Werner HM, Krakstad C, Birkeland E, Wik E, et al. (2012) Stratification based on high tumour cell content in fresh frozen tissue promotes selection of aggressive endometrial carcinomas. Histopathology 60: 516–519. doi: 10.1111/j.1365-2559.2011.04057.x
[41]
Galluzzi L, Maiuri MC, Vitale I, Zischka H, Castedo M, et al. (2007) Cell death modalities: classification and pathophysiological implications. Cell death and differentiation 14: 1237–1243. doi: 10.1038/sj.cdd.4402148
[42]
Taatjes DJ, Sobel BE, Budd RC (2008) Morphological and cytochemical determination of cell death by apoptosis. Histochemistry and cell biology 129: 33–43. doi: 10.1007/s00418-007-0356-9
[43]
McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, et al. (2005) Reporting recommendations for tumor marker prognostic studies (REMARK). Journal of the National Cancer Institute 97: 1180–1184. doi: 10.1093/jnci/dji237
[44]
Xiao H, Verdier-Pinard P, Fernandez-Fuentes N, Burd B, Angeletti R, et al. (2006) Insights into the mechanism of microtubule stabilization by Taxol. Proceedings of the National Academy of Sciences of the United States of America 103: 10166–10173. doi: 10.1073/pnas.0603704103
[45]
Arslan C, Sari E, Aksoy S, Altundag K (2011) Variation in hormone receptor and HER-2 status between primary and metastatic breast cancer: review of the literature. Expert opinion on therapeutic targets 15: 21–30. doi: 10.1517/14656566.2011.537260
[46]
Khasraw M, Brogi E, Seidman AD (2011) The need to examine metastatic tissue at the time of progression of breast cancer: is re-biopsy a necessity or a luxury? Current oncology reports 13: 17–25. doi: 10.1007/s11912-010-0137-9
[47]
Simmons C, Miller N, Geddie W, Gianfelice D, Oldfield M, et al. (2009) Does confirmatory tumor biopsy alter the management of breast cancer patients with distant metastases? Annals of oncology: official journal of the European Society for Medical Oncology/ESMO 20: 1499–1504. doi: 10.1093/annonc/mdp028
[48]
Krakstad C, Trovik J, Wik E, Engelsen IB, Werner HM, et al. (2012) Loss of GPER identifies new targets for therapy among a subgroup of ERalpha-positive endometrial cancer patients with poor outcome. British journal of cancer 106: 1682–1688.
[49]
Birkeland E, Wik E, Mjos S, Hoivik EA, Trovik J, et al. (2012) KRAS gene amplification and overexpression but not mutation associates with aggressive and metastatic endometrial cancer. British journal of cancer 107: 1997–2004.
[50]
Amir E, Clemons M, Purdie CA, Miller N, Quinlan P, et al. (2012) Tissue confirmation of disease recurrence in breast cancer patients: pooled analysis of multi-centre, multi-disciplinary prospective studies. Cancer treatment reviews 38: 708–714. doi: 10.1016/j.ctrv.2011.11.006
[51]
Amir E, Miller N, Geddie W, Freedman O, Kassam F, et al. (2012) Prospective study evaluating the impact of tissue confirmation of metastatic disease in patients with breast cancer. J Clin Oncol 30: 587–592. doi: 10.1200/jco.2010.33.5232
[52]
Harris L, Fritsche H, Mennel R, Norton L, Ravdin P, et al. (2007) American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol 25: 5287–5312. doi: 10.1200/jco.2007.14.2364