COX-2 induces IL-11 production in human breast cancer cells.
BACKGROUND
Cyclooxygenase-2 (COX-2) is overexpressed in 40% of human invasive breast cancers. Interleukin-11 (IL-11), a potent mediator of osteoclastogenesis, is involved in breast cancer metastasis to bone. Since breast cancers that overexpress COX-2 are associated with a higher rate of metastasis to bone, we hypothesized that COX-2 expression in tumor cells would induce IL-11.


METHODS
We transfected MCF-7 (poorly metastatic) and MDA-231 (highly metastatic) human breast cancer cell lines with COX-2 expression vectors. COX-2 overexpression was confirmed by Western blot and PGE(2) immunoassay, and IL-11 production was measured by immunoassay. We also used a nude mouse model to study COX-2 and IL-11 production from breast cancer cells that metastasized to bone. The bone-seeking clones (BSC) were isolated and cultured from the long bone metastases.


RESULTS
COX-2 transfection caused an approximately 5- to 6-fold increase in IL-11 production in both MCF-7 and MDA-231 cells. MDA-435S-COX2-BSC (cells isolated from bone metastasis) produced elevated levels of IL-11 and PGE2 (an important mediator of COX-2) as compared to the parental MDA-435S-COX2 cells. Furthermore, a treatment with low 1- to 2-microm concentration NS-398 or Celecoxib significantly reduced the production of IL-11 in COX-2-transfected MDA-231 cells, thus confirming the involvement of COX-2 in IL-11 induction.


CONCLUSIONS
COX-2-mediated production of IL-11 in breast cancer cells may be vital to the development of osteolytic bone metastases in patients with breast cancer, and a COX-2 inhibitor may be useful in inhibiting this process.
Singh
Balraj
B
Department of Surgical Oncology, University of Texas, M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Berry
Jacob A
JA
Shoher
Angela
A
Lucci
Anthony
A
D000818:Animals; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000556:secondary; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000502:physiology*; D005260:Female; D006801:Humans; D007118:Immunoassay; D017370:Interleukin-11 / Q000096:biosynthesis*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D017370:Interleukin-11; D051546:Cyclooxygenase 2