Cyclooxygenase-2 inhibition: effects on tumour growth, cell cycling and lymphangiogenesis in a xenograft model of breast cancer

• Published in: British journal of cancer 2007-02, Vol.96 (4), p.575-582
• Main Authors: Barnes, N L P, Warnberg, F, Farnie, G, White, D, Jiang, W, Anderson, E, Bundred, N J
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Apoptosis; Apoptosis - drug effects; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; breast; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Cancer Research; Celecoxib; Cell Cycle - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Cyclooxygenase 2 - biosynthesis; Cyclooxygenase 2 - drug effects; Cyclooxygenase 2 Inhibitors - pharmacology; Cyclooxygenase 2 Inhibitors - therapeutic use; cyclooxygenase-2; Drug Resistance; Epidemiology; Female; Gynecology. Andrology. Obstetrics; Humans; Immunohistochemistry; Kinases; lymphangiogenesis; Lymphangiogenesis - drug effects; Mammary gland diseases; Medical prognosis; Medical research; Medical sciences; MEDICIN; MEDICINE; Membrane Proteins - biosynthesis; Membrane Proteins - drug effects; Metastasis; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Medicine; Nonsteroidal anti-inflammatory drugs; Oncology; Proto-Oncogene Proteins c-akt - drug effects; Proto-Oncogene Proteins c-akt - metabolism; Pyrazoles - pharmacology; Pyrazoles - therapeutic use; Structure-Activity Relationship; Sulfonamides - pharmacology; Sulfonamides - therapeutic use; Translational Therapeutics; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0007-0920; 1532-1827; 1532-1827
• DOI: 10.1038/sj.bjc.6603593

Cyclooxygenase-2 (COX-2) is associated with poor-prognosis breast cancer. We used a nude mouse xenograft model to determine the effects of COX-2 inhibition in breast cancer. Oestrogen receptor (ER)-positive MCF7/HER2-18 and ER-negative MDAMB231 breast cancer cell lines were injected into nude mice and allowed to form tumours. Mice then received either chow containing Celecoxib (a COX-2 inhibitor) or control and tumour growth measured. Tumour proliferation, apoptosis, COX-2, lymphangiogenesis and angiogenesis were assessed by immunohistochemistry (IHC), Western blotting or Q-PCR. Celecoxib inhibited median tumour growth in MCF7/HER2-18 (58.7%, P =0.029) and MDAMB231 (46.3%, P =0.0002) cell lines compared to control. Cyclooxygenase-2 expression decreased following Celecoxib treatment (MCF7/HER2-18 median control 65.3% vs treated 22.5%, P =0.0001). Celecoxib increased apoptosis in MCF7/HER2-18 tumours (TUNEL 0.52% control vs 0.73% treated, P =0.0004) via inactivation of AKT (median pAKT ser473 57.3% control vs 35.5% treated, P =0.0001 – confirmed at Western blotting). Q-PCR demonstrated decreased podoplanin RNA (lymphangiogenesis marker) in the MCF7/HER2-18 – median 2.9 copies treated vs 66.6 control ( P =0.05) and MDAMB231-treated groups – median 160.7 copies vs 0.05 control copies ( P =0.015), confirmed at IHC. Cyclooxygenase-2 is associated with high levels of activated AKT ser473 and lymphangiogenesis in breast cancer. Cyclooxygenase-2 inhibition decreases tumour growth, and may potentially decrease recurrence, by inactivating AKT and decreasing lymphangiogenesis.