Autophagy inhibition augments the anticancer effects of epirubicin treatment in anthracycline-sensitive and -resistant triple-negative breast cancer.
OBJECTIVE
Triple-negative breast cancers (TNBC) are defined by a lack of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (ERBB2/HER2). Although initially responsive to chemotherapy, most recurrent TNBCs develop resistance, resulting in disease progression. Autophagy is a lysosome-mediated degradation and recycling process that can function as an adaptive survival response during chemotherapy and contribute to chemoresistance. Our goal was to determine whether autophagy inhibition improves treatment efficacy in TNBC cells in tumors either sensitive or refractory to anthracyclines.


METHODS
We used in vitro and in vivo models of TNBC using cell lines sensitive to epirubicin and other anthracyclines, as well as derivative lines, resistant to the same drugs. We assessed basal autophagy levels and the effects of chemotherapy on autophagy in parental and resistant cells. Applying various approaches to inhibit autophagy alone and in combination with chemotherapy, we assessed the effects on cell viability in vitro and tumor growth rates in vivo.


RESULTS
We demonstrated that epirubicin induced autophagic flux in TNBC cells. Epirubicin-resistant lines exhibited at least 1.5-fold increased basal autophagy levels and, when treated with autophagy inhibitors, showed a significant loss in viability, indicating dependence of resistant cells on autophagy for survival. Combination of epirubicin with the autophagy inhibitor hydroxychloroquine resulted in a significant reduction in tumor growth compared with monotherapy with epirubicin.


CONCLUSIONS
Autophagy inhibition enhances therapeutic response in both anthracycline-sensitive and -resistant TNBC and may be an effective new treatment strategy for this disease.
Authors' Affiliations: The Genome Sciences Centre; Department of Experimental Therapeutics; Medical Oncology, BC Cancer Agency; Interdisciplinary Oncology Program, Departments of Medicine and Pathology and Laboratory Medicine, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver; and Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
Suganthi
S
Chittaranjan
Authors' Affiliations: The Genome Sciences Centre; Department of Experimental Therapeutics; Medical Oncology, BC Cancer Agency; Interdisciplinary Oncology Program, Departments of Medicine and Pathology and Laboratory Medicine, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver; and Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, CanadaAuthors' Affiliations: The Genome Sciences Centre; Department of Experimental Therapeutics; Medical Oncology, BC Cancer Agency; Interdisciplinary Oncology Program, Departments of Medicine and Pathology and Laboratory Medicine, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver; and Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
Svetlana
S
Bortnik
Authors' Affiliations: The Genome Sciences Centre; Department of Experimental Therapeutics; Medical Oncology, BC Cancer Agency; Interdisciplinary Oncology Program, Departments of Medicine and Pathology and Laboratory Medicine, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver; and Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
Wieslawa H
WH
Dragowska
Authors' Affiliations: The Genome Sciences Centre; Department of Experimental Therapeutics; Medical Oncology, BC Cancer Agency; Interdisciplinary Oncology Program, Departments of Medicine and Pathology and Laboratory Medicine, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver; and Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, CanadaAuthors' Affiliations: The Genome Sciences Centre; Department of Experimental Therapeutics; Medical Oncology, BC Cancer Agency; Interdisciplinary Oncology Program, Departments of Medicine and Pathology and Laboratory Medicine, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver; and Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
Jing
J
Xu
Authors' Affiliations: The Genome Sciences Centre; Department of Experimental Therapeutics; Medical Oncology, BC Cancer Agency; Interdisciplinary Oncology Program, Departments of Medicine and Pathology and Laboratory Medicine, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver; and Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
Namal
N
Abeysundara
Authors' Affiliations: The Genome Sciences Centre; Department of Experimental Therapeutics; Medical Oncology, BC Cancer Agency; Interdisciplinary Oncology Program, Departments of Medicine and Pathology and Laboratory Medicine, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver; and Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
Amy
A
Leung
Authors' Affiliations: The Genome Sciences Centre; Department of Experimental Therapeutics; Medical Oncology, BC Cancer Agency; Interdisciplinary Oncology Program, Departments of Medicine and Pathology and Laboratory Medicine, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver; and Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, CanadaAuthors' Affiliations: The Genome Sciences Centre; Department of Experimental Therapeutics; Medical Oncology, BC Cancer Agency; Interdisciplinary Oncology Program, Departments of Medicine and Pathology and Laboratory Medicine, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver; and Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
Nancy E
NE
Go
Authors' Affiliations: The Genome Sciences Centre; Department of Experimental Therapeutics; Medical Oncology, BC Cancer Agency; Interdisciplinary Oncology Program, Departments of Medicine and Pathology and Laboratory Medicine, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver; and Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, CanadaAuthors' Affiliations: The Genome Sciences Centre; Department of Experimental Therapeutics; Medical Oncology, BC Cancer Agency; Interdisciplinary Oncology Program, Departments of Medicine and Pathology and Laboratory Medicine, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver; and Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
Lindsay
L
DeVorkin
Authors' Affiliations: The Genome Sciences Centre; Department of Experimental Therapeutics; Medical Oncology, BC Cancer Agency; Interdisciplinary Oncology Program, Departments of Medicine and Pathology and Laboratory Medicine, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver; and Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
Sherry A
SA
Weppler
Authors' Affiliations: The Genome Sciences Centre; Department of Experimental Therapeutics; Medical Oncology, BC Cancer Agency; Interdisciplinary Oncology Program, Departments of Medicine and Pathology and Laboratory Medicine, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver; and Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, CanadaAuthors' Affiliations: The Genome Sciences Centre; Department of Experimental Therapeutics; Medical Oncology, BC Cancer Agency; Interdisciplinary Oncology Program, Departments of Medicine and Pathology and Laboratory Medicine, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver; and Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, CanadaAuthors' Affiliations: The Genome Sciences Centre; Department of Experimental Therapeutics; Medical Oncology, BC Cancer Agency; Interdisciplinary Oncology Program, Departments of Medicine and Pathology and Laboratory Medicine, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver; and Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
Karen
K
Gelmon
Authors' Affiliations: The Genome Sciences Centre; Department of Experimental Therapeutics; Medical Oncology, BC Cancer Agency; Interdisciplinary Oncology Program, Departments of Medicine and Pathology and Laboratory Medicine, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver; and Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, CanadaAuthors' Affiliations: The Genome Sciences Centre; Department of Experimental Therapeutics; Medical Oncology, BC Cancer Agency; Interdisciplinary Oncology Program, Departments of Medicine and Pathology and Laboratory Medicine, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver; and Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
Donald T
DT
Yapp
Authors' Affiliations: The Genome Sciences Centre; Department of Experimental Therapeutics; Medical Oncology, BC Cancer Agency; Interdisciplinary Oncology Program, Departments of Medicine and Pathology and Laboratory Medicine, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver; and Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, CanadaAuthors' Affiliations: The Genome Sciences Centre; Department of Experimental Therapeutics; Medical Oncology, BC Cancer Agency; Interdisciplinary Oncology Program, Departments of Medicine and Pathology and Laboratory Medicine, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver; and Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, CanadaAuthors' Affiliations: The Genome Sciences Centre; Department of Experimental Therapeutics; Medical Oncology, BC Cancer Agency; Interdisciplinary Oncology Program, Departments of Medicine and Pathology and Laboratory Medicine, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver; and Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, CanadaAuthors' Affiliations: The Genome Sciences Centre; Department of Experimental Therapeutics; Medical Oncology, BC Cancer Agency; Interdisciplinary Oncology Program, Departments of Medicine and Pathology and Laboratory Medicine, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver; and Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
Marcel B
MB
Bally
Authors' Affiliations: The Genome Sciences Centre; Department of Experimental Therapeutics; Medical Oncology, BC Cancer Agency; Interdisciplinary Oncology Program, Departments of Medicine and Pathology and Laboratory Medicine, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver; and Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, CanadaAuthors' Affiliations: The Genome Sciences Centre; Department of Experimental Therapeutics; Medical Oncology, BC Cancer Agency; Interdisciplinary Oncology Program, Departments of Medicine and Pathology and Laboratory Medicine, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver; and Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, CanadaAuthors' Affiliations: The Genome Sciences Centre; Department of Experimental Therapeutics; Medical Oncology, BC Cancer Agency; Interdisciplinary Oncology Program, Departments of Medicine and Pathology and Laboratory Medicine, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver; and Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada sgorski@bcgsc.ca.
Sharon M
SM
Gorski
D000818:Animals; D018943:Anthracyclines / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D015251:Epirubicin / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051379:Mice; D064726:Triple Negative Breast Neoplasms / Q000473:pathology / Q000517:prevention & control*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D015251:Epirubicin