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Improved efficacy of mitochondrial disrupting agents upon inhibition of autophagy in a mouse model of BRCA1-deficient breast cancer

Yeo, Syn Kok et al.

Autophagy. Volume 14:Issue 7 (2018); pp 1214-1225 -- Taylor & Francis

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  • Title:
    Improved efficacy of mitochondrial disrupting agents upon inhibition of autophagy in a mouse model of BRCA1-deficient breast cancer
  • Author: Yeo, Syn Kok;
    Paul, Ritama;
    Haas, Michael;
    Wang, Chenran;
    Guan, Jun-Lin
  • Found In: Autophagy. Volume 14:Issue 7 (2018); pp 1214-1225
  • Journal Title: Autophagy
  • Subjects: Autophagy--Periodicals; Cell Death--Periodicals; Apoptosis--Periodicals; Autophagic vacuoles--Periodicals; Cell death--Periodicals; Degeneration (Pathology)--Periodicals; Lysosomes--Periodicals; Periodicals; Autophagy--BRCA1--breast cancer--metformin--mitochondria; Dewey: 571.936
  • Rights: legaldeposit
  • Publication Details: Taylor & Francis
  • Abstract: ABSTRACT:

    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.

  • Identifier: System Number: LDEAvdc_100067771696.0x000001; Journal ISSN: 1554-8627; 10.1080/15548627.2018.1460010
  • Publication Date: 2018
  • Physical Description: Electronic
  • Shelfmark(s): ELD Digital store

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