Aspirin Suppresses Breast Cancer Metastasis by Targeting Anoikis Resistance

Abstract

Background: Aspirin intake lowers the risk of breast cancer metastasis, but mechanisms remain unclear. Anoikis resistance has been recently implicated in metastasis. Here we investigated whether aspirin might prevent breast cancer metastasis by targeting anoikis resistance. MethodsA:noikis was induced by culturing breast cancer cells on 1% agar treated plate for 24 h, and apoptotic cell death was determined by Annexin V and PI staining. Chemoprevention of breast cancer metastasis was evaluated by using a 4T1 mouse mammary tumor model. Findings: Aspirin sensitized breast cancer cells to anoikis in vitro, and lowered the circulating tumor cells as well as distant metastasis in vivo. Thromboxane A2 (TXA2) pathway was identified as the relevant molecular target for aspirin in anoikis sensitization. Mechanistically, thromboxane A2 receptor (TP) was up-regulated in detached breast cancer cells, conferred anoikis resistance through Akt activation, thereby facilitated breast cancer metastasis to lung. Interpretation: TXA2 pathway plays a critical role in anoikis resistance, and might serve as potential target for chemoprevention of breast cancer metastasis. Funding Information: his work was supported by the National Natural Science Foundation of China (81773064, 31972973 and 32021005). Declaration of Interests: No potential conflicts of interest were disclosed. Ethics Approval Statement: All animal study was conducted under protocols approved by the Institutional Animal Ethics Committee of Jiangnan University. (Issue No. 20200430c0501101[020], 20190330c0700615[58]).