AKT isoforms have discrete expression in Triple Negative breast cancers and roles in cisplatin sensitivity

Khan, Sameer; Wadhwa, Bhumika; Paddar, Masroor; Malik, Fayaz; Mir, Sameer; Clarke, Philip A; Grabowska, Anna M; Vijay, Devanahalli G; Malik, Fayaz

Abstract

AKT, a serine threonine kinase, exists in three different isoforms and is known for regulating several biological processes including tumorigenesis. In this study, we investigated the expression and net effect of the individual isoforms in triple negative breast cancers and response to cisplatin treatment using cellular, mice models and clinical samples. Interestingly, analysis of the expressions of AKT isoforms in clinical samples showed relatively higher expression of AKT1 in primary tissues; whereas lung and liver metastatic samples showed elevated expression of AKT2. Similarly, triple-negative breast cancer cell lines, BT-549 and MDA-MB-231, with high proliferative and invasive properties, displayed higher expression levels of AKT1/2. By modulating AKT isoform expression in MCF-10A and BT-549 cell lines, we found that presence of AKT2 was associated with invasiveness, stemness and sensitivity to drug treatment. It was observed that the silencing of AKT2 suppressed the cancer stem cell populations (CD44high CD24low, ALDH1), mammosphere formation, invasive and migratory potential in MCF-10A and BT-549 cells. It was further demonstrated that loss of function of AKT1 isoform is associated with reduced sensitivity towards cisplatin treatment in triple-negative breast cancers cellular and syngeneic mice models. The decrease in cisplatin treatment response in shAKT1 cells was allied with the upregulation in the expression of transporter protein ABCG2, whereas silencing of ABCG2 restored cisplatin sensitivity in these cells through AKT/SNAIL/ABCG2 axis. In conclusion, our study demonstrated the varied expression of AKT isoforms in triple-negative breast cancers and also confirmed differential role of isoforms in stemness, invasiveness and response towards the cisplatin treatment.

• Journal Article Type: Article
• Acceptance Date: Sep 9, 2019
• Online Publication Date: Nov 10, 2020
• Publication Date: Nov 10, 2020
• Deposit Date: Dec 11, 2019
• Publicly Available Date: Aug 25, 2022
• Electronic ISSN: 1949-2553
• Publisher: Impact Journals
• Peer Reviewed: Peer Reviewed
• Volume: 11
• Pages: 4178-4194
• DOI: https://doi.org/10.18632/oncotarget.27746
• Keywords: AKT isoform; CSCs; ABCG2; Drug Resistance; TNBCs
• Public URL: https://nottingham-repository.worktribe.com/output/3535656
• Publisher URL: https://www.oncotarget.com/article/27746/