Angiogenic molecule expression is downregulated in effusions from breast cancer patients.
The objective of this study was to analyze site-related expression of angiogenic molecules in breast carcinoma, with the aim of characterizing phenotypic alterations along the clinical progression from primary tumor to pleural effusion. A total of 49 malignant pleural effusions and 68 corresponding solid tumors were studied for protein and mRNA expression of vascular endothelial growth factor (VEGF) and its receptor KDR, interleukin-8 (IL-8), basic fibroblast growth factor (bFGF) and the alphaV integrin subunit using immunohistochemistry, mRNA in situ hybridization (ISH) and reverse transcription polymerase chain reaction (RT-PCR). Expression was analyzed for possible association with mRNA expression of the Ets-1 and PEA3 transcription factors. The predictive value of angiogenic molecules, PEA3 and Ets-1, and clinical parameters was analyzed for 18 patients. ISH showed the presence of VEGF, IL-8 and bFGF mRNA in the majority of specimens, irrespective of anatomic site (p > 0.05). However, protein expression of IL-8 and bFGF was lower in effusions compared to primary tumors (p = 0.001 for IL-8, p < 0.001 for bFGF). Expression of alphaV integrin showed an opposite change, with higher level in effusions compared to primary tumors (p = 0.03). bFGF and alphaV integrin expression in effusions was also altered compared to lymph node metastases (p = 0.041 and p = 0.016, respectively). IL-8 and Ets-1 (p = 0.035) and VEGF and PEA3 (p = 0.026) mRNA was co-expressed in effusions. In univariate survival analysis, bFGF protein expression in effusions (p = 0.015), PEA3 mRNA expression in primary tumors (p = 0.02) and previous radiation therapy (p = 0.034) predicted shorter disease-free survival. PEA mRNA expression in primary tumors (p = 0.002) and previous chemotherapy (p = 0.048) predicted poor overall survival, with a similar trend for advanced disease stage at diagnosis (p = 0.05). Our data provide evidence regarding molecular changes that occur along the progression of breast carcinoma from primary tumor to effusion, and suggest altered requirement of angiogenic factors in body cavities. The poor disease-free survival for patients with bFGF-positive effusions suggests a role for this growth factor in mediating tumor survival rather than angiogenesis at this site.
Konstantinovsky
Sophya
S
Department of Pharmacology and Experimental Therapeutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
Nielsen
Søren
S
Vyberg
Mogens
M
Kvalheim
Gunnar
G
Nesland
Jahn M
JM
Reich
Reuven
R
Davidson
Ben
B
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D042501:Angiogenic Proteins / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000401:mortality / Q000503:physiopathology*; D016022:Case-Control Studies; D018572:Disease-Free Survival; D015536:Down-Regulation; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039564:Integrin alphaV / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008875:Middle Aged; D016066:Pleural Effusion, Malignant / Q000166:cytology; D050783:Proto-Oncogene Proteins c-ets / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015996:Survival Rate; D014157:Transcription Factors / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D042501:Angiogenic Proteins; D039564:Integrin alphaV; D016209:Interleukin-8; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; C065788:transcription factor PEA3; D016222:Fibroblast Growth Factor 2