Abstract A42: Small molecule activators of p53 for the treatment of inflammatory breast cancer

Abstract

Abstract Although rare, inflammatory breast cancer (IBC) is the most aggressive form of breast cancer with a 5 year survival of 40% compared to 85% for ductal carcinoma in situ. The standard therapy for this disease is chemo- and radiation therapy; however there are currently no targeted therapies for IBC. Histopathology data suggests that 40–70% of IBC tumors express wild type p53, while approximately 40% are estrogen receptor positive (ER+). The disease is characterized by early and diffuse intravasation of the breast lymphatic vessels by the tumor cells which form emboli that block the drainage of the ducts leading to swelling of the affected breast and erythema. Efforts to increase survival from this often lethal disease have been hindered by the paucity of model systems for studying the underlying biology of IBC. We have used the SUM 149PT and SUM 190PT cell lines, which were originally derived from IBC to investigate the utility of two histone deacetylase (HDAC) inhibitors (CG-1521 and TSA), alone and in combination with anti-estrogens as a novel therapy for the disease. In prostate cancer cell lines CG-1521 has been shown to acetylate p53 at Lys 373 and induce cell death, while TSA induces specific acetylation of Lys382 and induces cell cycle arrest. Both SUM 149PT and SUM 190PT express ERα and ERβ, although neither cell line requires estradiol for cell growth. SUM149PT cells express wild type p53, while the SUM 190PT express a truncated isoform of the protein. CG-1521 induces DNA fragmentation and cell death in both cell lines. While TSA also induces cell death in the SUM 149PT cells, it only induces cell cycle arrest in the SUM 190PT cells, which we attribute to the truncation of the p53 protein. Treatment of SUM149PT cells with low doses of either tamoxifen or CG-1521 individually does not induce apoptosis but in combination, causes a substantial decrease in cell number and indicates that the two compounds act synergistically in this context. These data suggest that HDAC inhibitors such as CG-1521 and TSA, which target specific Lys residues in p53 may be useful for the treatment of IBC. Citation Information: Cancer Res 2009;69(23 Suppl):A42.