title: Identification of breast cancer cell subtypes sensitive to ATG4B inhibition.
abstract: Autophagy, a lysosome-mediated degradation and recycling process, functions in advanced malignancies to promote cancer cell survival and contribute to cancer progression and drug resistance. While various autophagy inhibition strategies are under investigation for cancer treatment, corresponding patient selection criteria for these autophagy inhibitors need to be developed. Due to its central roles in the autophagy process, the cysteine protease ATG4B is one of the autophagy proteins being pursued as a potential therapeutic target. In this study, we investigated the expression of ATG4B in breast cancer, a heterogeneous disease comprised of several molecular subtypes. We examined a panel of breast cancer cell lines, xenograft tumors, and breast cancer patient specimens for the protein expression of ATG4B, and found a positive association between HER2 and ATG4B protein expression. We showed that HER2-positive cells, but not HER2-negative breast cancer cells, require ATG4B to survive under stress. In HER2-positive cells, cytoprotective autophagy was dependent on ATG4B under both starvation and HER2 inhibition conditions. Combined knockdown of ATG4B and HER2 by siRNA resulted in a significant decrease in cell viability, and the combination of ATG4B knockdown with trastuzumab resulted in a greater reduction in cell viability compared to trastuzumab treatment alone, in both trastuzumab-sensitive and -resistant HER2 overexpressing breast cancer cells. Together these results demonstrate a novel association of ATG4B positive expression with HER2 positive breast cancers and indicate that this subtype is suitable for emerging ATG4B inhibition strategies.
authors.affiliation: The Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.|Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Bortnik
authors.affiliation: The Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.|Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada.
authors.forename: Courtney
authors.initials: C
authors.lastname: Choutka
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.|Vancouver General Hospital, BC Cancer Agency, Vancouver, BC, Canada.|Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Hugo M
authors.initials: HM
authors.lastname: Horlings
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.|Vancouver General Hospital, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Samuel
authors.initials: S
authors.lastname: Leung
authors.affiliation: Radiation Biology Unit - Department of Integrative Oncology, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Baker
authors.affiliation: The Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.|Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada.
authors.forename: Chandra
authors.initials: C
authors.lastname: Lebovitz
authors.affiliation: Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Wieslawa H
authors.initials: WH
authors.lastname: Dragowska
authors.affiliation: The Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Go
authors.affiliation: Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC, Canada.|Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.|Centre for Drug Research and Development, Vancouver, BC, Canada.
authors.forename: Marcel B
authors.initials: MB
authors.lastname: Bally
authors.affiliation: Radiation Biology Unit - Department of Integrative Oncology, BC Cancer Agency, Vancouver, BC, Canada.
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Minchinton
authors.affiliation: Medical Oncology, BC Cancer Agency, Vancouver, BC, Canada.|Department of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Karen A
authors.initials: KA
authors.lastname: Gelmon
authors.affiliation: The Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada.|Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC, Canada.|Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada.|Centre for Cell Biology, Development, and Disease, Simon Fraser University, Burnaby, BC, Canada.
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Gorski
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D000071183:Autophagy-Related Proteins / Q000096:biosynthesis*; D001943:Breast Neoplasms / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000096:biosynthesis*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000502:physiology; D005260:Female; D064593:Heterografts; D006801:Humans; D051379:Mice; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis; D000068878:Trastuzumab / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000071183:Autophagy-Related Proteins; D003546:Cysteine Endopeptidases; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C507524:ATG4B protein, human
keywords: ATG4B; HER2; autophagy; breast cancer; trastuzumab