title: MUC1-C Stabilizes MCL-1 in the Oxidative Stress Response of Triple-Negative Breast Cancer Cells to BCL-2 Inhibitors.
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.
authors.affiliation: Dana-Farber Cancer Institute Harvard Medical School Boston, MA 02215, USA.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Hiraki
authors.affiliation: Dana-Farber Cancer Institute Harvard Medical School Boston, MA 02215, USA.
authors.forename: Yozo
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Dana-Farber Cancer Institute Harvard Medical School Boston, MA 02215, USA.
authors.forename: Maroof
authors.initials: M
authors.lastname: Alam
authors.affiliation: Dana-Farber Cancer Institute Harvard Medical School Boston, MA 02215, USA.
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Hinohara
authors.affiliation: Dana-Farber Cancer Institute Harvard Medical School Boston, MA 02215, USA.
authors.forename: Masanori
authors.initials: M
authors.lastname: Hasegawa
authors.affiliation: Dana-Farber Cancer Institute Harvard Medical School Boston, MA 02215, USA.
authors.forename: Caining
authors.initials: C
authors.lastname: Jin
authors.affiliation: Dana-Farber Cancer Institute Harvard Medical School Boston, MA 02215, USA.
authors.forename: Surender
authors.initials: S
authors.lastname: Kharbanda
authors.affiliation: Dana-Farber Cancer Institute Harvard Medical School Boston, MA 02215, USA.
authors.forename: Donald
authors.initials: D
authors.lastname: Kufe
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D005260:Female; D006801:Humans; D018396:Mucin-1 / Q000235:genetics / Q000378:metabolism*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism*; D009596:Nitrophenols / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects* / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology; D055550:Protein Stability / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: C501332:ABT-737; D000814:Aniline Compounds; C000595707:BCL2 protein, human; D001713:Biphenyl Compounds; C579095:MCL1 protein, human; C060192:MUC1 protein, human; D018396:Mucin-1; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; C528561:navitoclax