Cancer cells face a wide array of environmental and cellular stresses. As biologists begin to appreciate the importance of effective stress adaptation during cancer initiation and progression, this has led to the intriguing hypothesis that tumor cells under duress are uniquely dependent on specific pathways that promote cellular fitness. Interestingly, these same pathways are comparatively dispensable in normal cells, which previously led to their premature dismissal as housekeeping functions. This intriguing idea, recently termed “non-oncogene addiction,” forms the biological rationale behind the growing number of unbiased screens to identify molecules engaged in “synthetic lethal” interactions with established oncogenes and tumor suppressors (Luo et al., 2009
As part of this research arena, increasing scrutiny has been directed toward modulating fundamental cellular stress response pathways to prevent the survival and expansion of tumor cells. One such process is macroautophagy, a tightly regulated lysosomal degradation process conserved in all eukaryotic cells. The degradation and recycling of proteins, organelles, and other cytoplasmic components is vital for the maintenance of cellular homeostasis and is commonly observed in cells under various forms of duress (Levine and Kroemer, 2008
). Two principal mechanisms of protein degradation have been described—the ubiquitin-proteasome system, for the degradation of short-lived proteins; and autophagy, which mediates the delivery of long-lived cytoplasmic proteins and organelles to the lysosome for destruction (Levine and Kroemer, 2008
). Importantly, one should recognize that multiple routes of autophagic degradation exist within cells, including: 1) macroautophagy, in which cytoplasmic contents are sequestered in double membrane autophagosomes, and subsequently delivered to the lysosome; 2) microautophagy, where cytoplasm is directly engulfed by lysosomal membrane; and 3) chaperone-mediated autophagy, where proteins with a specific signal sequence are transported to the lysosomal lumen by a receptor-mediated process (Mizushima et al., 2008
). Of these routes, macroautophagy has been most extensively studied for its potential functions in cancer; as a result, this process will be the exclusive focus of this review and henceforth be referred to as autophagy (Roy and Debnath, 2010
Autophagy is tightly regulated by a limited number of highly conserved genes called ATG
ophaGy related gene) that were first identified in yeast (Klionsky et al., 2003
). These landmark studies have led to numerous recent breakthroughs in mammals demonstrating a critical role for autophagy in both physiological and pathological processes, including cancer initiation and progression (Mizushima et al., 2008
). Bulk degradation of cellular material through autophagy allows cells to recycle both nutrients and energy during starvation and stress; in this regard, autophagy is proposed to function as a “battery” that buys cells valuable time, allowing them to survive if the stressor is removed in a timely manner (Lum et al., 2005
; Roy and Debnath, 2010
). This indispensable contribution of autophagy as a stress response mechanism is poignantly illustrated by studies in mice, in which the genetic deletion of critical ATGs results in neonatal lethality within a day after birth (Komatsu et al., 2005
; Kuma et al., 2004
). Autophagy is also activated in response to multiple stresses relevant for cancer progression, including nutrient starvation, the unfolded protein response (ER stress), and hypoxia; in addition, it is observed upon treatment of cancers with a wide spectrum of cytotoxic and targeted chemotherapeutic agents (Kondo et al., 2005
). Because autophagy most often functions as a survival mechanism in response to these diverse stressors, one can speculate that autophagy functions entirely as a tumor-promoting mechanism by promoting the cellular fitness of cancer cells under various forms of duress. However, genetic evidence indicates otherwise; rather, autophagy can exert important tumor suppressive functions (Roy and Debnath, 2010
). Clearly, to effectively target autophagy for therapeutic purposes against cancer, several fundamental issues must be addressed.
In this review, I will first summarize recent advances in our understanding of the mechanics of autophagy. Next, I will overview the tumor-suppressive and promoting functions of autophagy and how they both dictate oncogenic transformation in vitro and cancer progression in vivo. Though findings most germane to breast cancer will be highlighted, it is important to recognize that our current understanding in this field is largely derived from results from a broad spectrum of model systems and tumor types. Lastly, I will speculate on specific circumstances in which autophagy may be most effectively targeted to improve clinical outcomes in breast cancer.