STAT3-Mediated Autophagy Dependence Identifies Subtypes of Breast Cancer Where Autophagy Inhibition Can Be Efficacious

Abstract

Autophagy is a protein and organelle degradation pathway that is involved in diverse diseases including cancer. Recent evidence suggests that autophagy is a cell survival mechanism in tumor cells and that its inhibition especially in combination with other therapy could be beneficial but it remains unclear if all cancer cells behave the same way when autophagy is inhibited. We inhibited autophagy in a panel of breast cancer cell lines and found that some of them are dependent on autophagy for survival even in nutrient rich conditions without any additional stress while others need autophagy only when stressed. Survival under unstressed conditions is due to cell type specific autophagy regulation of STAT3 activity and this phenotype is enriched in triple negative cell lines. This autophagy-dependency affects response to therapy because autophagy inhibition reduced tumor growth in vivo in autophagy-dependent but not in autophagy-independent breast tumors while combination treatment with autophagy inhibitors and other agent was preferentially synergistic in autophagy-dependent cells. These results imply that autophagy-dependence represents a tumor cell specific characteristic where autophagy inhibition will be more effective. Moreover, our results suggest that autophagy inhibition might be a potential therapeutic strategy for triple negative breast cancers, which currently lack an effective targeted treatment.

Recent insights into the function of autophagy in cancer

“…Second, human cancer cell lines can be unaffected by autophagy suppression (e.g., Maycotte et al 2014;Mandelbaum et al 2015). Human cancer cell lines often tolerate genome-editing approaches that delete Atg genes when grown in two-dimensional (2D) culture with replete culture medium , which is in contrast to the findings from spontaneously arising tumors.…”

The role of STAT3 in autophagy

“…However, in established tumor cells, which are constantly exposed to mutations, radiation, chemotherapy or targeted agents, autophagy may act as an additional means for survival. 3 Although the exact role of autophagy is debatable in different tumor models or in different pathological conditions, certain tumors are proposed to be 'autophagy addicted,' 4 and numerous crosstalk occurs between autophagy and other cancer-promoting pathways. 5 STAT3 (signal transducer and activator of transcription 3 [acute-phase response factor]) is a latent transcription factor that mediates extracellular signals such as cytokines and growth factors through interaction with polypeptide receptors at the cell surface.…”

Non-cell-autonomous Effects of Autophagy Inhibition in Tumor Cells Promote Growth of Drug-resistant Cells

“…We were interested to test if autophagy inhibition, which is being tested in the clinic as a chemosensitization strategy as a means to improve cancer therapy, could affect the behavior of drug-resistant cells. Because cancer cells can show both growth inhibitory and stimulatory effects to autophagy inhibition (Guo et al, 2011;Maycotte et al, 2014), treatment with pharmacological autophagy inhibitors that would affect both drug sensitive and resistant cells equally is unable to test rigorously for non-cellautonomous effects of autophagy in a heterogeneous tumor cell population. We previously reported that autophagy inhibition sensitizes cancer cells to TRAIL-induced apoptosis by making it easier for the cancer cells to activate caspases after mitochondrial membrane disruption (Thorburn et al, 2014b).…”