PMID- 29938573
OWN - NLM
STAT- MEDLINE
DCOM- 20191009
LR  - 20211204
IS  - 1554-8635 (Electronic)
IS  - 1554-8627 (Print)
IS  - 1554-8627 (Linking)
VI  - 14
IP  - 7
DP  - 2018
TI  - Improved efficacy of mitochondrial disrupting agents upon inhibition of autophagy 
      in a mouse model of BRCA1-deficient breast cancer.
PG  - 1214-1225
LID - 10.1080/15548627.2018.1460010 [doi]
AB  - Breast cancer is a heterogeneous disease, and stratification of patients is 
      fundamental to the success of treatment modalities. Breast tumors deficient in 
      BRCA1 are mostly associated with basal-like breast cancers and targeted 
      therapeutics for this disease subtype are still lacking. In order to address 
      whether macroautophagy/autophagy inhibition will be effective in BRCA1-deficient 
      mammary tumors, we generated mice with conditional deletion of an essential 
      autophagy gene, Rb1cc1, along with Brca1 and Trp53, through utilization of the 
      K14-Cre transgene. We found that Rb1cc1 deletion suppressed tumorigenesis in the 
      BRCA1-deficient model when compared to wild type and heterozygous Rb1cc1 
      controls. However, in contrast to previous studies in the mouse mammary tumor 
      virus (MMTV)-polyoma middle T antigen (PyMT) model, tumor growth and the 
      distribution of histological subtypes were not affected by loss of RB1CC1. 
      Interestingly, loss of RB1CC1 decreased mitochondrial mass and oxidative 
      respiratory capacity of these tumor cells, along with a decrease in the 
      phosphorylation of MTOR substrates and transcript levels of genes involved in 
      mitochondrial biogenesis. Importantly, we observed an increased sensitivity to 
      mitochondrial disrupting agents upon loss of RB1CC1. Consequently, our data 
      showed that combination of an autophagy inhibitor, spautin-1, along with a 
      mitochondrial complex I inhibitor, metformin, was more effective in limiting 
      oxidative respiratory capacity, colony-forming ability and tumor growth. 
      Altogether, our results indicate that inhibition of autophagy can increase the 
      benefits of metformin treatment in BRCA1-deficient breast cancers.
FAU - Yeo, Syn Kok
AU  - Yeo SK
AD  - a Department of Cancer Biology , University of Cincinnati College of Medicine , 
      Cincinnati , OH , USA.
FAU - Paul, Ritama
AU  - Paul R
AD  - a Department of Cancer Biology , University of Cincinnati College of Medicine , 
      Cincinnati , OH , USA.
FAU - Haas, Michael
AU  - Haas M
AD  - a Department of Cancer Biology , University of Cincinnati College of Medicine , 
      Cincinnati , OH , USA.
FAU - Wang, Chenran
AU  - Wang C
AD  - a Department of Cancer Biology , University of Cincinnati College of Medicine , 
      Cincinnati , OH , USA.
FAU - Guan, Jun-Lin
AU  - Guan JL
AD  - a Department of Cancer Biology , University of Cincinnati College of Medicine , 
      Cincinnati , OH , USA.
LA  - eng
GR  - R01 NS103981/NS/NINDS NIH HHS/United States
GR  - R03 NS097887/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20180720
PL  - United States
TA  - Autophagy
JT  - Autophagy
JID - 101265188
RN  - 0 (Autophagy-Related Proteins)
RN  - 0 (BRCA1 Protein)
RN  - 0 (Benzylamines)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Quinazolines)
RN  - 0 (Rb1cc1 protein, mouse)
RN  - 0 (spautin-1)
RN  - 9100L32L2N (Metformin)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - *Autophagy/drug effects
MH  - Autophagy-Related Proteins
MH  - BRCA1 Protein/*metabolism
MH  - Benzylamines/pharmacology
MH  - Cell Line, Tumor
MH  - Disease Models, Animal
MH  - Female
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Intracellular Signaling Peptides and Proteins/deficiency/metabolism
MH  - Mammary Neoplasms, Animal/genetics/*metabolism/*pathology
MH  - Metformin/pharmacology
MH  - Mice
MH  - Mitochondria/drug effects/metabolism/*pathology
MH  - Models, Biological
MH  - Organelle Biogenesis
MH  - Oxidative Stress
MH  - Phosphorylation/drug effects
MH  - Quinazolines/pharmacology
MH  - Substrate Specificity/drug effects
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Treatment Outcome
PMC - PMC6103709
OTO - NOTNLM
OT  - Autophagy
OT  - BRCA1
OT  - breast cancer
OT  - metformin
OT  - mitochondria
EDAT- 2018/06/26 06:00
MHDA- 2019/10/11 06:00
PMCR- 2019/07/20
CRDT- 2018/06/26 06:00
PHST- 2018/06/26 06:00 [pubmed]
PHST- 2019/10/11 06:00 [medline]
PHST- 2018/06/26 06:00 [entrez]
PHST- 2019/07/20 00:00 [pmc-release]
AID - 1460010 [pii]
AID - 10.1080/15548627.2018.1460010 [doi]
PST - ppublish
SO  - Autophagy. 2018;14(7):1214-1225. doi: 10.1080/15548627.2018.1460010. Epub 2018 
      Jul 20.