Triple Negative Breast Cancer Cells Have Higher Dependence On Mitophagy For Their Survival As Compared To Hormone Positive Breast Cancer Cells

Autophagy is a key pathway utilised by the cells to clear the dysfunctional cellular components and maintain homeostasis. However cancer cells having defective apoptosis, deploy autophagy as a survival mechanism by limiting tumor necrosis and metabolic stress. Autophagy has been reported to be upregulated in triple negative breast cancers which are categorized as the most aggressive breast cancers with poor prognosis. Nevertheless the exact mechanism of autophagic upregulation in TNBC is still elusive. Therefore analyzing pathways specifically altered in these tumors might provide better targets for therapeutic intervention. Results: In the present study we observed higher basal autophagy in TNBC cell line MDA MB 231 as compared to triple positive MCF7 cells as analyzed by the presence of higher number of GFP-LC3 puncta in the former. Treatment with 20μM of autophagy inhibitor chloroquine for 48 hrs led to significant cell death in TNBC cell line as compared to MCF7 whereas treatment with 20μM of PI3K inhibitor wortamannin did not significantly affected the survival of TNBC and MCF7 cells. Further the analysis of autophagy markers revealed higher LC3B and Beclin1 levels as compared to ATG5 and ATG7 levels in MDA MB 231 cells both at mRNA and protein levels as analyzed by qPCR and western blot. Also the knockdown of ATG7 by ATG7 shRNA did not significantly affected the survival of TNBC cells. Conclusion: Thus in this study we aim to highlight the difference in the expression of autophagy markers and the effect of autophagy inhibitors wherein only late phase of autophagy seems to significantly upregulated in TNBC. The difference can be attributed to the dependence of TNBC cells upon ‘late phase autophagy’ or particularly ‘mitophagy’ that is crucial for rapid clearance of misfolded proteins and dysfunctional mitochondria as has been reported in TNBCs. Further study to dissect the mechanism of selective upregulation of ‘late phase autophagy’or ‘mitophagy’ in TNBC might provide novel targets for treatment strategies in these breast cancers. Citation Format: Bhawana Dikshit, Aakansha Rai, Soumya Sinha Roy. Triple negative breast cancer cells have higher dependence on mitophagy for their survival as compared to hormone positive breast cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 988. doi:10.1158/1538-7445.AM2015-988