Relationship between cyclooxygenase-2 and human epidermal growth factor receptor 2 in vascular endothelial growth factor C up-regulation and lymphangiogenesis in human breast cancer.
Both cyclooxygenase (COX)-2 and human epidermal growth factor receptor (HER)-2 promote breast cancer progression; however, the relationship between the two molecules remains unclear. We utilized human breast cancer tissues and cell lines to examine whether COX-2 and HER-2 played independent or interdependent roles in vascular endothelial growth factor (VEGF)-C up-regulation and lymphangiogenesis. A paired correlation of immunodetectable levels of COX-2, VEGF-C, and HER-2 proteins and lymphovascular density (LVD; D2-40-immunolabeled) in 55 breast cancer specimens revealed a positive correlation between COX-2 and HER-2 irrespective of clinicopathological status. However COX-2 alone positively correlated with LVD. In 10 independent specimens, mRNA levels showed a positive correlation between HER-2 and COX-2 or VEGF-C but not LYVE-1 (lymphovascular endothelial marker). These findings implicate COX-2, but not HER-2, in breast cancer-associated lymphangiogenesis. Manipulation of the COX-2 or HER-2 genes in breast cancer cell lines varying widely in COX-2 and HER-2 expression revealed a direct role of COX-2 and an indirect COX-2 dependent role of HER-2 in VEGF-C up-regulation: (i) high VEGF-C expression in high COX-2/low HER-2 expressing MDA-MB-231 cells was reduced by siRNA-mediated down-regulation of COX-2, but not HER-2; (ii) integration of HER-2 in these cells simultaneously up-regulated COX-2 protein as well as VEGF-C secretion; and (iii) low VEGF-C secretion by high HER-2/low COX-2 expressing SK-BR-3 cells was stimulated by COX-2 overexpression. These findings of the primary role of COX-2 and the COX-2-dependent role of HER-2, if any, in VEGF-C up-regulation and lymphangiogenesis suggest that COX-2 inhibitors may abrogate lymphatic metastasis in breast cancer irrespective of HER-2 status.
Bhattacharjee
Rabindra N
RN
Department of Anatomy,The University of Western Ontario, London, Ontario, Canada.
Timoshenko
Alexander V
AV
Cai
Jing
J
Lala
Peeyush K
PK
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D042583:Lymphangiogenesis; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism
D051546:Cyclooxygenase 2; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D042582:Vascular Endothelial Growth Factor C; D033921:Vesicular Transport Proteins; C119248:LYVE1 protein, human; C508053:ERBB2 protein, human