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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.
Abbreviations
| BPK | = | brca1F/F;trp53F/F;K14-Cre |
| BRCA1 | = | BRCA1, DNA repair associated |
| CSC | = | cancer stem cell |
| LP | = | luminal progenitors |
| MMTV | = | mouse mammary tumor virus |
| MTOR | = | mechanistic target of rapamycin kinase |
| OCR | = | oxygen consumption rate |
| PBS | = | phosphate-buffered saline |
| PyMT | = | polyoma middle T antigen |
| RB1CC1/FIP200 | = | RB1 inducible coiled-coil 1 |
| SQSTM1 | = | sequestosome 1 |
Acknowledgments
We would like to thank Dylan Gierok and Rose Copley for help with genotyping and the University of Cincinnati LAMS staff for their support with regards to mouse colony maintenance and husbandry. Brca1F/F Trp53F/F mice were kindly provided by Dr. Jos Jonkers from the Netherlands Cancer Institute. We appreciate the help from Glenn Doerman in preparation of figures. We are grateful to members of the Guan lab for critical appraisal and suggestions in the preparation of this manuscript. This research was supported by NIH grants to J.-L. Guan.
Disclosure statement
No potential conflict of interest was reported by the authors.
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