Abstract P1-06-09: The role of miR-155-5p in MSI2 induced metastasis of prolonged DEHP exposed triple-negative breast cancer cells

Abstract Phthalate leaching, environmental pollution,and human exposure is major issue. Endocrine disrupting effects of phthalate exposure on human health are well documented affecting hormonal balance, reproductive system, endometriosis, and is a suspected carcinogen. Continuous and prolonged use of plastic products leads to direct human exposure to phthalates, a problem observed in developing countries. In an attempt to mimic continuous human exposure to phthalates, we investigated the effects of long term DEHP exposure at physiological concentration on breast cancer cells. Long-term DEHP exposure enhanced migration and invasion in triple negative breast cancer cells in vitro and in vivo zebrafish xenograft assay indicating ER independent activity of DEHP. NGS identified oncogenic protein, Musashi RNA binding protein2 (MSI2) as metastasis regulator in DEHP exposed breast cancer cells. Elevated MSI2 expression induced metastatic potential through MSI2/Vimentin interaction, EMT and PI3K/Akt/NFκB/MMP9 axis activation. Besides metastatic properties MSI2 overexpression increased stem cell potential in triple negative breast cancer cells. Novel MSI2-Vimentin protein-protein interaction was evidenced in DEHP exposed breast cancer cells highlighting new function of MSI2 apart from RNA-binding and translation regulation. Reduced expression of miR-155-5p was found to negatively regulate MSI2 expression in DEHP exposed breast cancercells. miR-155-5p mimic treatment reduced expression of MSI2 and MSI2 mediated metastasis. MSI2 knockdown reversed EMT and PI3K/Akt/NFκB/MMP9 axis induced metastasis in vitro and in vivo zebrafish xenograft in DEHP exposed breast cancer cells, showing no effect non DEHP exposed breast cancer cells. Organ specific metastasis activity was observed in invivo mouse breast cancer metastasis model showing lung metastasis in DEHP exposed breast cancer cell implanted mice. MSI2 depletion reduced lung metastasis in vivo, however no effectof MSI2 depletion observed on proliferation and tumor size. MSI2 targeting might serve as a promising strategy to overcome highly metastatic breast cancer and to limit stem cell like cancer progression. Keywords: Breast cancer;DEHP; long phthalate exposure; ATP-binding transporter proteins; drug resistance; tariquidar; NGS; MSI2; metastasis; EMT; Vimentin; miR-155-5p;stemness Citation Format: Mahendra Gunvantrao Jadhao, Chien Chih Chiu. The role of miR-155-5p in MSI2 induced metastasis of prolonged DEHP exposed triple-negative breast cancer cells [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-06-09.