Abstract 4329: Modulation of metastatic behavior in breast cancers harboring p53 mutations

Abstract

Abstract The mutation of p53 generally occurs during the later stages of cancer and leads to the increased metastatic potential of triple negative (ER_/PR_/Her2_) breast cancer. The low survival rates of advanced metastatic cancer make it critical not only to understand the mechanisms underlying the functional implications of p53 mutation, but also to identify ways to regulate its impact in cancer cell physiology. We have previously described the design, synthesis, and evaluation of a stabilized α-helix of p53 (SAH-p53) capable of inhibiting the p53-HDM2 and p53-HDMX interactions in order to restore the functionality of p53. Despite having low expression of both HDM2 and HDMX and mutations in p53, SAH-p53 treatment of the triple negative breast cancer cell lines MDA-MB-231 and HS578T results in a modest decrease in proliferative activity. While mutant p53 is known to promote metastatic behavior of breast cancer cells, the propensity of triple negative breast cancer cells to migrate and invade through Matrigel in the presence of EGF was decreased by treatment with SAH-p53. The anti-proliferative and anti-migratory effects of SAH-p53 treatment are independent of each other, yet both are accompanied by an alteration in cell morphology that includes the loss of cell membrane integrity and actin cytoskeletal organization. The surface level of β1 integrin, which is typically kept constant by mutant p53, is decreased in the presence of SAH-p53, pointing to possible alterations in integrin recycling. SAH-p53 also causes a change in the localization of the adhesion protein and stem cell marker CD44. Moreover, it has been suggested that mutant p53 enhances invasive properties by interacting with and inhibiting isoforms of p63, which have been implicated in the regulation of cell adhesion. Treatment of the triple negative breast cancer cells with a stabilized α-helix of p63 showed a significant decrease in cell viability as well as an enhanced inhibition of migration when treated simultaneously with SAH-p53. Targeted therapy for triple negative breast cancer is currently very limited and patients must rely on standard chemotherapeutic regimens. These data show that the use of SAH-p53 and SAH-p63 peptides provides a novel avenue to study the molecular interactions that drive metastatic behavior originated by p53 gain-of-function mutations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4329. doi:1538-7445.AM2012-4329