P3-01-07: A Murine Xenograft Model for the Study of Ciclooxygenase-2 Expression and Function in Human Breast Cancer.

Abstract

Abstract BACKGROUND: ciclooxygenase-2 (COX-2) has been suggested as a necessary component of the cellular and molecular mechanisms behind breast cancer cell motility and invasion The potential therapeutic benefit of COX-2 inhibitors in a range of cancers is being seen as a great promise however, there have been recent concerns about potential cardiotoxicity. Thus, there is an urgency to develop new inhibitors exhibiting a better risk/benefit ratio. Acyl-CoA synthetase 4 (ACSL4), belongs to a five-member familyof enzymes that esterifies mainly arachidonic acid into acyl-CoA. We have provided first-time evidence demonstrating that, ACSL4 is the key enzyme that regulates the induction of COX-2, the production of prostaglandin E2 (PGE2) and the proliferation and metastatic potential of breast cancer cells. Therefore, the aim of the study was the development of an in vivo model of human breast tumor xenografts for the study of the regulation of COX-2 expression and action. RESULTS: stable transfection of MCF-7 cells with ACSL4 cDNA under the control of tetracycline (MCF-7 Tet-off-ACSL4) resulted in a significant increase in the expression of COX-2. The increment in COX-2 expression registered in MCF-7 Tet-off-ACSL4 cells is accompanied with an increase in the production of PGE2, and the proliferation and metastatic potential of cancer cells. Next, we tested whether the injection of MCF-7 Tet-off/ACSL4 cells into nude mice resulted in tumor development. The results of those experiments demonstrate that MCF-7 Tet-off/ACSL4 cells develop into murine mammary tumors whereas cells transfected with the MCF-7 Tet-off empty vector did not. Interestingly, treatment of nude mice with tetracycline resulted in tumor growth inhibition. The results show that the sole transfection of ACSL4 results in a phenotype change that endows the cells with the capacity to develop into tumors when injected into nude mice. Tumor volume (TV) at day 70 reached 468.4 ± 189.3mm3. Treatment with tetracycline reduced TV to 189.3 ± 65.9mm3 (p<0.05). The growth rate between days 45–70 was 12.30 mm3/day. Tumors were classified as Basal-like subtypes. We have also observed an inhibition of proliferation and migration of MDA-MB-231 cell cultures when exposed to a combination of ACSL4 and COX-2 inhibitors. Interestingly, the compounds assayed markedly reduced cell proliferation and migration at concentrations that are less effective when used alone. These results point to an effect that has the advantage of exposing the cells to lower drug concentrations. CONCLUSION: Based on our results, we hypothesize that ACSL4 and COX-2 could constitute potential therapeutic targets for the control of tumor growth. Our animal model of mammary tumors constitutes a proper platform for the study of those therapies. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-01-07.