Abstract 3331: CD24 promotes HER2 signaling pathways and CD24 inhibition sensitizes anti-HER2 therapy in breast cancer

Abstract Human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancers are treated with HER2-targeted agents such as trastuzumab and lapatinib, which suppress HER2-initiated activation of the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) cascades. CD24 is a glycosyl phosphatidylinositol (GPI)-anchored membrane protein and its overexpression is correlated with a poor prognosis in breast cancer patients. It has been reported that CD24 tends to be highly expressed in the HR-HER2+ breast cancer subgroup, which is negative for the hormone receptors (HRs) and positive for HER2. To determine the relationship between CD24 and HER2, we overexpressed HER2 in MDA-MB-231 breast cancer cells, which were negative for CD24 and HER2. We found that the expression of CD24 was increased by the overexpression of HER2. Flow cytometry analysis showed that the expression of CD24 was higher in the HER2-positive fraction than in the HER2-negative fraction. Conversely, in BT474 cells which express both CD24 and HER2, CD24 knockdown reduced the expression of HER2, while the knockdown of HER2 did not affect the expression of CD24. Furthermore, the knockdown of CD24 decreased the phosphorylation of Akt, which is known as a downstream molecule of PI3K and is related to cell survival. Accordingly, CD24 plays an important role in the regulation of the HER2-initiated signaling pathway. Based on these findings, we speculated that the expression of CD24 promotes a resistance to HER2-targeted therapies, leading to tumor progression in HER2-overexpressing cancers. We found that the knockdown of CD24 enhanced the sensitivity to lapatinib treatment. Consequently, we suggest using an anti-CD24 therapy to enhance the HER2-targeted therapy. Citation Format: Yoshimi Arima, Mari Hosonaga, Hideyuki Saya. CD24 promotes HER2 signaling pathways and CD24 inhibition sensitizes anti-HER2 therapy in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3331. doi:10.1158/1538-7445.AM2014-3331