Abstract 1211: Role of anchorage-independence in signaling pathway activation and cell survival in invasive breast cancer cell lines

Abstract

Abstract Resistance to anoikis - apoptosis induced by loss of matrix anchorage - is a key step in the metastatic process. In several cancer cell types including breast cancer cells, the anoikis-suppressing effect appears to be mediated by the PI3-kinase/Akt and MAP kinase signaling pathways. The aim of this study was to determine the involvement of signaling pathways in anoikis resistance in metastatic breast cancer cell lines. To study anoikis resistance, metastatic MDA-MB-231 and 4T1 cells were cultured on poly-HEMA-coated plates. Cell death was determined by detecting the sub-diploid population, by flow cytometry. Western analysis was used to assess the levels of phospho-Akt, phospho-p38 and cleaved-caspase-3. Our results show that loss of anchorage in MDA-231 cells reduces phospho-Akt levels, whereas in 4T1 cells - under both adherent and non-adherent conditions - the elevated level of phospho-Akt was not modified. Nevertheless, 4T1 cells undergo anoikis, which was dependent in part on the cleavage of caspase-3. In contrast, MDA-MB-231 cells were anoikis-resistant. Anoikis resistance correlated with the activation of p38 MAP-kinase. p38 phosphorylation was reduced in non-adherent 4T1 cells, whereas there was significantly higher levels of phosphorylated p38 in non-adherent than adherent MDA-MB-231 cells. The activation of p38 MAP kinase has been implicated in SDF1-CXCR4 signaling. One recent study has shown that CXCR4 inhibits anoikis in MDA-MB-231 cells, suggesting that CXCR4 or p38 blockade may induce anoikis in breast cancer. Thus our findings show that two metastatic breast cancer cell lines exhibit different sensitivity to anoikis, which is potentially associated with p38 MAP-kinase activity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1211.