Cyclooxygenase-2 expression in primary breast cancers predicts dissemination of cancer cells to the bone marrow

Abstract

Purpose 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.

A multicenter randomized phase II study of sequential epirubicin/cyclophosphamide followed by docetaxel with or without celecoxib or trastuzumab according to HER2 status, as primary chemotherapy for localized invasive breast cancer patients

“…While this first analysis does not suggest increase pCR, however, longer follow-up will be necessary to ascertain reduction in the metastatic rate. As suggested by Lucci et al, COX2 produced in primary breast cancer cells may be vital to the initial development of bone marrow micrometastasis that may subsequently lead to osteolytic bone metastases in patients with breast cancer, and COX2 inhibitors may be useful in halting this process [16].…”

“…COX-2 is frequently over-expressed in breast cancer, and associated with unfavorable outcomes. Over-expression of COX2 in breast cancer cell lines increases cell migration and invasion [16]. Celecoxib is a COX-2 inhibitor with anti-angiogenic and pro-apoptotic activity.…”

Cyclooxygenase-2 expression in non-metastatic triple-negative breast cancer patients

“…The majority of the studies employed immunohistochemistry and monoclonal antibodies to assess COX-2 protein expression in primary breast carcinomas and COX-2 positivity was identified in 33-58% of the cases (24)(25)(26)(27)(28)(29)(31)(32)(33)(34). COX-2 expression is frequently associated with high histological grade and large tumor size (24)(25)(26)(27)(28)30,32,33) and, to a lesser degree, negative ER status (24,26,27,30,31,33).…”

Does regional anaesthesia and analgesia or opioid analgesia influence recurrence after primary cancer surgery? An update of available evidence

“…[137][138][139][140][141] In murine models of breast cancer, COX-2 has been shown to be involved in osteoclastogenesis (via IL-11) [138] and stimulation of osteoclasts to resorb bone (via PGE2 and IL-8). [139] It has also been associated with increased tumourgenicity and clonogenicity, conferring genomic instability and changes in cell cycle regulation, including resistance to anoikis, as well as resistance to chemotherapeutic agents ( including doxorubicin).…”