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

Abstract

// Hussein F. Aqbi 1 , Liliya Tyutyunyk-Massey 2 , Rebecca C. Keim 1, 3 , Savannah E. Butler 1, 3 , Theresa Thekkudan 2 , Supriya Joshi 4 , Timothy M. Smith 1 , Dipankar Bandyopadhyay 3, 5 , Michael O. Idowu 3, 6 , Harry D. Bear 3, 7 , Kyle K. Payne 8 , David A. Gewirtz 2, 3 and Masoud H. Manjili 1, 3, 6, 9 1 Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, 23298, VA, USA 2 Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, 23298, VA, USA 3 Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, 23298, VA, USA 4 Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, 23298, VA, USA 5 Department of Biostatistics, Virginia Commonwealth University School of Medicine, Richmond, 23298, VA, USA 6 Department of Pathology, Virginia Commonwealth University School of Medicine, Richmond, 23298, VA, USA 7 Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, 23298, VA, USA 8 Department of Immunology, Moffitt Cancer Center, Tampa, 33612, FL, USA 9 VCU Institute of Molecular Medicine, Virginia Commonwealth University School of Medicine, Richmond, 23298, VA, USA Correspondence to: David A. Gewirtz, email: david.gewirtz@vcuhealth.org Masoud H. Manjili, email: masoud.manjili@vcuhealth.org 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 (ATG5 KD ), 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, ATG5 KD 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.