Abstract 2242: The MAPK and PI3K signaling pathways in breast cancer: Crosstalk mechanisms and the effect on cell proliferation

Abstract

Abstract The purpose of the current study is to assess crosstalk between the mitogen-activated protein kinase (MAPK) and the phosphatidylinositol 3-kinase (PI3K) pathways in breast cancer. More specifically, the goal is to investigate the interaction between the extracellular signal regulated kinases 1/2 and 5 (ERK1/2 and ERK5) and Akt and how these kinases act in concert to promote sustained proliferation in a breast cancer model. The MAPK and PI3K pathways mediate numerous cellular processes, including differentiation, growth, proliferation, and survival. To date, most related studies have focused on assessment of the crosstalk mechanisms between ERK1/2 and Akt, while the interplay of ERK5 has remained largely unstudied. Breast cancer patients with increased levels of ERK5 have been found to have a poorer prognosis than patients with lower levels, warranting further investigation of this kinase. The interaction between ERK5 and ERK1/2, as well as between ERK5 and Akt, and how these signaling mechanisms act in conjunction to promote cell proliferation in breast cancer cells remains to be elucidated. The BT-474 (ER+/PR+/HER2+) and MDA-MB-231 (ER-/PR-/HER2-) human breast cancer cell lines were utilized to examine ERK1/2, ERK5 and Akt activation following treatment with ERK and Akt inhibitors or siRNA for these kinases, respectively. Western blot analysis was performed to determine expression and activation of the kinases. An MTT assay was used to assess changes in cell proliferation following kinase inhibition for 12, 24, 48, 72 and 96 hours. In vivo studies utilizing the transgenic MMTV-neu mouse model were also performed. In the BT-474 cell line, inhibition of Akt resulted in increased ERK1/2 and ERK5 expression and activation. Interestingly, the increases in both total and phosphorylated ERK1/2 and ERK5 following Akt-inhibition were dose-dependent, meriting further study. Excised mammary tumors from our animal model demonstrated an age-dependent increase in both ERK1/2 and ERK5. Notably, an age-dependent decrease in Akt was also observed, supporting the hypothesis that crosstalk between these pathways may exist. Future studies involving dual kinase inhibition are planned to further assess crosstalk and proliferation. The data obtained from these studies indicate the presence of crosstalk between the ERK1/2, ERK5 and Akt pathways. A better understanding of this crosstalk may lead to patient-specific drug regimens to decrease the cytotoxic effects of chemotherapeutics and improve patient mortality. 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 2242. doi:1538-7445.AM2012-2242