Cyclooxygenase-2 expression in primary breast cancers predicts dissemination of cancer cells to the bone marrow.
OBJECTIVE
Cyclooxygenase-2 (COX2) plays a role in breast cancer progression at various stages starting from pre-malignant phenotype to clinical metastasis. Breast cancer metastasizes commonly to the bone and preclinical studies suggest an involvement of COX2 in this process. Detection of disseminated tumor cells in the bone marrow of patients at the time of surgery correlates with the subsequent development of clinical bone metastasis. Therefore, to investigate whether COX2 is important for breast cancer metastasis in humans, we analyzed COX2 protein expression by immunostaining of primary tumors from 112 operable stages I, II, or III patients and determined its correlation with bone marrow micrometastasis (BMM).


METHODS
We detected COX2 protein in primary tumors by immunostaining with a monoclonal antibody, and tumor cells present in the bone marrow by immunostaining for epithelial cytokeratins and by morphological criteria.


RESULTS
COX2 expression in primary breast cancer correlated with BMM in a highly statistically significant manner (P = 0.006). Our statistical analyses of correlations of the COX2 positivity in primary tumor with other clinically relevant indicators revealed that COX2 positivity correlates with high nuclear grade (P = 0.0004). Furthermore, we were able to detect COX2 protein in BMM by immunostaining.


CONCLUSIONS
These studies indicate that COX2 produced in primary breast cancer cells may be vital to the initial development of BMM that may subsequently lead to osteolytic bone metastases in patients with breast cancer, and that COX2 inhibitors may be useful in halting this process.
Lucci
Anthony
A
Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, 77030, USA. alucci@mdanderson.org
Krishnamurthy
Savitri
S
Singh
Balraj
B
Bedrosian
Isabelle
I
Meric-Bernstam
Funda
F
Reuben
James
J
Broglio
Kristine
K
Mosalpuria
Kailash
K
Lodhi
Ashutosh
A
Vincent
Laura
L
Cristofanilli
Massimo
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D019046:Bone Marrow Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000556:secondary; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000235:genetics* / Q000473:pathology; D009367:Neoplasm Staging
D014408:Biomarkers, Tumor; D051546:Cyclooxygenase 2