MUC1-C Stabilizes MCL-1 in the Oxidative Stress Response of Triple-Negative Breast Cancer Cells to BCL-2 Inhibitors

• Published in: Scientific reports Vol. 6; no. 1; p. 26643
• Main Authors: Hiraki, Masayuki, Suzuki, Yozo, Alam, Maroof, Hinohara, Kunihiko, Hasegawa, Masanori, Jin, Caining, Kharbanda, Surender, Kufe, Donald
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 24.05.2016
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Bcl protein; Bcl-2 protein; Bcl-x protein; Breast cancer; Drug resistance; Mcl-1 protein; Mucin; Oxidative stress; Reactive oxygen species
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep26643

Aberrant expression of myeloid cell leukemia-1 (MCL-1) is a major cause of drug resistance in triple-negative breast cancer (TNBC) cells. Mucin 1 (MUC1) is a heterodimeric oncoprotein that is aberrantly overexpressed in most TNBC. The present studies show that targeting the oncogenic MUC1 C-terminal subunit (MUC1-C) in TNBC cells with silencing or pharmacologic inhibition with GO-203 is associated with downregulation of MCL-1 levels. Targeting MUC1-C suppresses the MEK → ERK and PI3K → AKT pathways, and in turn destabilizes MCL-1. The small molecules ABT-737 and ABT-263 target BCL-2, BCL-XL and BCL-w, but not MCL-1. We show that treatment with ABT-737 increases reactive oxygen species and thereby MUC1-C expression. In this way, MUC1-C is upregulated in TNBC cells resistant to ABT-737 or ABT-263. We also demonstrate that MUC1-C is necessary for the resistance-associated increases in MCL-1 levels. Significantly, combining GO-203 with ABT-737 is synergistic in inhibiting survival of parental and drug resistant TNBC cells. These findings indicate that targeting MUC1-C is a potential strategy for reversing MCL-1-mediated resistance in TNBC.