Cyclooxygenase-2 directly induces MCF-7 breast tumor cells to develop into exponentially growing, highly angiogenic and regionally invasive human ductal carcinoma xenografts

Abstract

Based on our studies demonstrating first time evidence that the cyclooxygenase-2 (Cox-2) enzyme is abundant within invasive human breast tumors, we developed a clonally derived human breast tumor cell clone designated as MCF-7/Cox-2 Clone 10 by transfection of human Cox-2 cDNA into slow growing, Cox-2 null, non-metastatic MCF-7 human breast tumor cells. The present studies evaluated the biological characteristics of the MCF-7/Cox-2 Clone 10 human breast tumors compared to the characteristics of MCF-7/empty vector control tumors when grown in vivo following injection of 5x10(6) tumor cells into mammary fat pads of ovariectomized female Crl:Nu-Foxn1(nu) mice implanted with slow release 17-beta estradiol pellets. At 60 days after tumor cell injection, MCF-7/Cox-2 Clone 10 human breast tumors were 4-fold greater (p < 0.01) in volume than MCF-7/empty vector control tumors. MCF-7/Cox-2 Clone 10 human breast tumor xenografts were highly angiogenic based on histological observation of large-bore blood vessels, which was confirmed by immunohistochemical staining with anti-CD-31 antibody and quantitation of mean vessel density. MCF-7/Cox-2 Clone 10 human breast tumor cells were present within regional lymph nodes adjacent to mammary fat pads with their local invasion confirmed by Western blotting of Cox-2-protein. This unique Cox-2-dependent breast tumor model rapidly produces large, angiogenic, locally invasive human breast tumor xenografts in mammary fat pads of ovariectomized female Crl:Nu-Foxn1(nu) mice at 42-60 days which recapitulate human breast ductal carcinomas. This unique model may be invaluable as a means to evaluate preclinical safety and efficacy of novel adjuvant therapies for women with metastastic breast cancer including prostanoid receptor antagonists, newly developed anti-angiogenic therapies, as well as other novel approaches for targeting and destruction of human breast tumors and their vasculature.