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

Masayuki Hiraki,Surender Kharbanda,Caining Jin,Donald Kufe,Yozo Suzuki,Masanori Hasegawa,Maroof Alam,Kunihiko Hinohara

doi:10.1038/srep26643

Abstract

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.

Highlights

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We found that stable silencing of Mucin 1 (MUC1)-C with a MUC1shRNA is associated with downregulation of myeloid cell leukemia-1 (MCL-1) expression (Fig. 1A)
The present results demonstrate that silencing MUC1 C-terminal subunit (MUC1-C) in triplenegative breast cancer (TNBC) cells results in downregulation of MCL-1 expression

Summary

Introduction

The Harvard community has made this article openly available. Please share how this access benefits you. 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. 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. MCL-1 protects TNBC cells from death in response to the BH3 mimetic, ABT-737, which targets BCL-2, BCL-XL and BCL-w, but not MCL-110,11. The overexpression of MCL-1 has been associated in part with mechanisms that regulate MCL-1 stability In this regard, MCL-1 contains two proline, glutamic acid, serine and threonine (PEST) sequences that target proteins for degradation[17]. Little is known about the upstream signals that promote upregulation of MCL-1 in TNBC cells

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