Abstract 2634: Investigating the chemotherapeutic effects of aspirin in mutant PIK3CA breast cancer

Abstract

Although aspirin is primarily administered as an antipyretic and analgesic, numerous observational and randomized clinical trials have suggested a potential chemotherapeutic use. Recently, two independent studies demonstrated that aspirin use is associated with superior survival in colorectal cancer patients with mutant-PIK3CA but not among those with the wild-type gene. Despite these seminal observations, the molecular basis for this phenomenon remains poorly understood. Furthermore, whether this observation occurs in breast cancer is unknown. Given that (1) mutation of PIK3CA, the gene encoding the catalytic subunit of the phosphoinositide 3-kinase (PI 3-K) is highly prevalent in breast cancer and that (2) aspirin use is associated with a decrease in breast cancer mortality and distant recurrence, the relationship between PI 3-K pathway activation and the protective benefit of aspirin in breast cancer was investigated. Here, we utilize both PIK3CA mutant breast cancer cell lines and a well-characterized system of immortalized mammary epithelial cells stably expressing either wild-type and mutant PIK3CA E545K and H1047R respectively. Mutant PIK3CA breast cancer cells show a dose-dependent decrease in cell viability with increasing concentration of aspirin/salicylate. In these cells, co-treatment of aspirin with PI 3-K pathway inhibitors BYL719 or BKM120 caused a more significant decrease on cell growth compared to each single agent alone. In 3D culture, MCF10A cells expressing mutant PIK3CA-H1047R showed greater sensitivity to aspirin compared to cells expressing wild-type PIK3CA. Gene expression profiling and quantitative qRT-PCR was employed to identify and validate mutant PIK3CA-regulated genes respectively. Many of these genes were associated with inflammation; among them was the PTGS2 gene which encodes for cyclooxygenase-2 (COX-2). We observed that mutant PIK3CA regulates cyclooxygenase-2 (COX-2) mRNA and protein expression as well as production of prostaglandin E2α (PGE2α). Expression of mutant PIK3CA also increases phosphorylation of IKKβ and IκB; increases mTORC1 signaling and reduces AMPK activity. This is abrogated upon pharmacologic inhibition of mutant PIK3CA with BYL719 and BKM120. Notably, both aspirin and its metabolite salicylate can inhibit these PIK3CA-induced pathways and activate AMPK signaling. An understanding of these key survival and metabolic signaling pathways, which are modulated by aspirin, may help to explain aspirin's beneficial effect in PIK3CA-mutant breast cancers. Given the growing interest in personalized medicine, this pre-clinical study may provide insight for the stratification of patients who are most likely to benefit from adjuvant aspirin therapy.

Citation Format: Whitney Henry, Alex Toker. Investigating the chemotherapeutic effects of aspirin in mutant PIK3CA breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2634. doi:10.1158/1538-7445.AM2015-2634