This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Linderholm, B. K. Articles by Bergh, J. Search for Related Content PubMed PubMed Citation Articles by Linderholm, B. K. Articles by Bergh, J.

The Expression of Vascular Endothelial Growth Factor Correlates with Mutant p53 and Poor Prognosis in Human Breast Cancer¹

Department of Oncology, Radiumhemmet, Karolinska Institute and Hospital, SE-181 87 Stockholm, Sweden [B. K. L., T. L., S. K., J. B.]; Department of Cancer Epidemiology, Akademiska Hospital, Uppsala University, SE-751 85 Uppsala, Sweden [L. H.]; Institution of Oncology, Umeå University, SE-901 85 Umeå, Sweden [R. H.]; and Virco United Kingdom, Cambridge, England [J. L.]

Wild-type p53 protein has been shown to inhibit angiogenesis through thrombospondin in the preclinical setting. Here, we determined the associations between the expression of the angiogenic factor vascular endothelial growth factor (VEGF) and the p53 status, including different mutation sites and types, in primary breast cancer. Cytosols from 224 primary breast cancer patients were analyzed with an enzyme immunoassay for determination of human VEGF₁₆₅ protein content. p53 status was determined by cDNA-based sequencing of the entire coding region, by immunohistochemistry (IHC), and by a p53 luminometric immunoassay (LIA) method. Statistically significant associations was found between higher VEGF content and non-wild-type p53 status for all methods; sequence-based data (P = 0.0019), IHC data (P = 0.0068), and the LIA method (r = 0.427; P > 0.001). Highest VEGF values were detected in tumors with p53 insertions, deletions, and stop codon mutations (P = 0.0043). Combining p53 status and VEGF content resulted in additional prognostic information, relapse-free survival (RFS; P = 0.0377), overall survival (OS; P = 0.0319), and breast cancer corrected survival (BCCS; P = 0.0292). In multivariate analysis, the relative hazard increased when the VEGF data were added to the p53 status, with a relative hazard of 1.7 for RFS and 3.0 for BCCS, compared with 1.1 for RFS and 1.4 for BCCS among the patients with either high VEGF content or p53 mutation. Higher VEGF content was statistically significantly correlated with a worse outcome for patients with estrogen receptor-positive tumors receiving adjuvant tamoxifen: RFS (P = 0.0471), OS (P = 0.0134), BCCS (P = 0.0064), as well as in multivariate analysis with point estimates of 3.4 and 2.1 for BCCS and RFS, respectively. VEGF expression is related to p53 status in human breast cancer patients. Combining VEGF with p53 status resulted in better prognostic prediction.

This article has been cited by other articles:

				A. V. Ivshina, J. George, O. Senko, B. Mow, T. C. Putti, J. Smeds, T. Lindahl, Y. Pawitan, P. Hall, H. Nordgren, et al. Genetic Reclassification of Histologic Grade Delineates New Clinical Subtypes of Breast Cancer Cancer Res., November 1, 2006; 66(21): 10292 - 10301. [Abstract] [Full Text] [PDF]

				S M Hyder Sex-steroid regulation of vascular endothelial growth factor in breast cancer. Endocr. Relat. Cancer, September 1, 2006; 13(3): 667 - 687. [Abstract] [Full Text] [PDF]

				M. Abdelrahim and S. Safe Cyclooxygenase-2 Inhibitors Decrease Vascular Endothelial Growth Factor Expression in Colon Cancer Cells by Enhanced Degradation of Sp1 and Sp4 Proteins Mol. Pharmacol., August 1, 2005; 68(2): 317 - 329. [Abstract] [Full Text] [PDF]

				M. J. Goodheart, J. M. Ritchie, S. L. Rose, J. P. Fruehauf, B. R. De Young, and R. E. Buller The Relationship of Molecular Markers of p53 Function and Angiogenesis to Prognosis of Stage I Epithelial Ovarian Cancer Clin. Cancer Res., May 15, 2005; 11(10): 3733 - 3742. [Abstract] [Full Text] [PDF]

				A. Hoeben, B. Landuyt, M. S. Highley, H. Wildiers, A. T. Van Oosterom, and E. A. De Bruijn Vascular Endothelial Growth Factor and Angiogenesis Pharmacol. Rev., December 1, 2004; 56(4): 549 - 580. [Abstract] [Full Text] [PDF]

				G. E. Konecny, Y. G. Meng, M. Untch, H.-J. Wang, I. Bauerfeind, M. Epstein, P. Stieber, J.-M. Vernes, J. Gutierrez, K. Hong, et al. Association between HER-2/neu and Vascular Endothelial Growth Factor Expression Predicts Clinical Outcome in Primary Breast Cancer Patients Clin. Cancer Res., March 1, 2004; 10(5): 1706 - 1716. [Abstract] [Full Text] [PDF]

				D. Santini, B. Vincenzi, G. Dicuonzo, G. Avvisati, C. Massacesi, F. Battistoni, M. Gavasci, L. Rocci, M. C. Tirindelli, V. Altomare, et al. Zoledronic Acid Induces Significant and Long-Lasting Modifications of Circulating Angiogenic Factors in Cancer Patients Clin. Cancer Res., August 1, 2003; 9(8): 2893 - 2897. [Abstract] [Full Text] [PDF]

				T. Abe, K. Terada, H. Wakimoto, R. Inoue, E. Tyminski, R. Bookstein, J. P. Basilion, and E. A. Chiocca PTEN Decreases in Vivo Vascularization of Experimental Gliomas in Spite of Proangiogenic Stimuli Cancer Res., May 1, 2003; 63(9): 2300 - 2305. [Abstract] [Full Text] [PDF]

				A. J. Bauer, A. Patel, R. Terrell, K. Doniparthi, M. Saji, M. Ringel, R. M. Tuttle, and G. L. Francis Systemic Administration of Vascular Endothelial Growth Factor Monoclonal Antibody Reduces the Growth of Papillary Thyroid Carcinoma in a Nude Mouse Model Ann. Clin. Lab. Sci., April 1, 2003; 33(2): 192 - 199. [Abstract] [Full Text] [PDF]

				E. M. J. J. Berns, J. G. M. Klijn, M. P. Look, N. Grebenchtchikov, R. Vossen, H. Peters, A. Geurts-Moespot, H. Portengen, I. L. van Staveren, M. E. Meijer-van Gelder, et al. Combined Vascular Endothelial Growth Factor and TP53 Status Predicts Poor Response to Tamoxifen Therapy in Estrogen Receptor-positive Advanced Breast Cancer Clin. Cancer Res., April 1, 2003; 9(4): 1253 - 1258. [Abstract] [Full Text] [PDF]

				M. Stoner, B. Saville, M. Wormke, D. Dean, R. Burghardt, and S. Safe Hypoxia Induces Proteasome-Dependent Degradation of Estrogen Receptor {alpha} in ZR-75 Breast Cancer Cells Mol. Endocrinol., October 1, 2002; 16(10): 2231 - 2242. [Abstract] [Full Text] [PDF]

				E. S. J. M. de Bont, V. Fidler, T. Meeuwsen, F. Scherpen, K. Hahlen, and W. A. Kamps Vascular Endothelial Growth Factor Secretion Is an Independent Prognostic Factor for Relapse-free Survival in Pediatric Acute Myeloid Leukemia Patients Clin. Cancer Res., September 1, 2002; 8(9): 2856 - 2861. [Abstract] [Full Text] [PDF]

				D. Santini, B. Vincenzi, G. Avvisati, G. Dicuonzo, F. Battistoni, M. Gavasci, A. Salerno, V. Denaro, and G. Tonini Pamidronate Induces Modifications of Circulating Angiogenetic Factors in Cancer Patients Clin. Cancer Res., May 1, 2002; 8(5): 1080 - 1084. [Abstract] [Full Text] [PDF]

				Y.-T. Tai, K. Podar, D. Gupta, B. Lin, G. Young, M. Akiyama, and K. C. Anderson CD40 activation induces p53-dependent vascular endothelial growth factor secretion in human multiple myeloma cells Blood, February 15, 2002; 99(4): 1419 - 1427. [Abstract] [Full Text] [PDF]

				E. Fosslien Molecular Pathology of Cyclooxygenase-2 in Cancer-induced Angiogenesis Ann. Clin. Lab. Sci., October 1, 2001; 31(4): 325 - 348. [Abstract] [Full Text] [PDF]