Oncotarget

Research Papers:

Autophagy-deficient breast cancer shows early tumor recurrence and escape from dormancy

Hussein F. Aqbi _, Liliya Tyutyunyk-Massey, Rebecca C. Keim, Savannah E. Butler, Theresa Thekkudan, Supriya Joshi, Timothy M. Smith, Dipankar Bandyopadhyay, Michael O. Idowu, Harry D. Bear, Kyle K. Payne, David A. Gewirtz and Masoud H. Manjili

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Oncotarget. 2018; 9:22113-22122. https://doi.org/10.18632/oncotarget.25197

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Abstract

Hussein F. Aqbi1, Liliya Tyutyunyk-Massey2, Rebecca C. Keim1,3, Savannah E. Butler1,3, Theresa Thekkudan2, Supriya Joshi4, Timothy M. Smith1, Dipankar Bandyopadhyay3,5, Michael O. Idowu3,6, Harry D. Bear3,7, Kyle K. Payne8, David A. Gewirtz2,3 and Masoud H. Manjili1,3,6,9

1Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, 23298, VA, USA

2Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, 23298, VA, USA

3Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, 23298, VA, USA

4Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, 23298, VA, USA

5Department of Biostatistics, Virginia Commonwealth University School of Medicine, Richmond, 23298, VA, USA

6Department of Pathology, Virginia Commonwealth University School of Medicine, Richmond, 23298, VA, USA

7Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, 23298, VA, USA

8Department of Immunology, Moffitt Cancer Center, Tampa, 33612, FL, USA

9VCU Institute of Molecular Medicine, Virginia Commonwealth University School of Medicine, Richmond, 23298, VA, USA

Correspondence to:

David A. Gewirtz, email: [email protected]

Masoud H. Manjili, email: [email protected]

Keywords: breast cancer; autophagy; tumor dormancy; tumor escape and relapse; cancer immunotherapy

Received: March 15, 2018     Accepted: April 07, 2018     Published: April 24, 2018

ABSTRACT

Breast cancer patients who initially respond to cancer therapies often succumb to distant recurrence of the disease. It is not clear why people with the same type of breast cancer respond to treatments differently; some escape from dormancy and relapse earlier than others. In addition, some tumor clones respond to immunotherapy while others do not. We investigated how autophagy plays a role in accelerating or delaying recurrence of neu-overexpressing mouse mammary carcinoma (MMC) following adriamycin (ADR) treatment, and in affecting response to immunotherapy. We explored two strategies: 1) transient blockade of autophagy with chloroquine (CQ), which blocks fusion of autophagosomes and lysosomes during ADR treatment, and 2) permanent inhibition of autophagy by a stable knockdown of ATG5 (ATG5KD), which inhibits the formation of autophagosomes in MMC during and after ADR treatment. We found that while CQ prolonged tumor dormancy, but that stable knockdown of autophagy resulted in early escape from dormancy and recurrence. Interestingly, ATG5KD MMC contained an increased frequency of ADR-induced polyploid-like cells and rendered MMC resistant to immunotherapy. On the other hand, a transient blockade of autophagy did not affect the sensitivity of MMC to immunotherapy. Our observations suggest that while chemotherapy-induced autophagy may facilitate tumor relapse, cell-intrinsic autophagy delays tumor relapse, in part, by inhibiting the formation of polyploid-like tumor dormancy.


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