The Multifaceted Roles of Autophagy in Tumors—Implications for Breast Cancer

Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, 513 Parnassus Ave, HSW450B, San Francisco, CA 94143, USA.
Journal of Mammary Gland Biology and Neoplasia (Impact Factor: 4.53). 09/2011; 16(3):173-87. DOI: 10.1007/s10911-011-9223-3
Source: PubMed


Autophagy is an evolutionarily conserved lysosomal degradation process that is crucial for adaptation to stress as well as in cellular homeostasis. In cancer, our current understanding has uncovered multifaceted roles for autophagy in tumor initiation and progression. Although genetic evidence corroborates a critical role for autophagy as a tumor suppressor mechanism, autophagy can also promote the survival and fitness of advanced tumors subject to stress, which has important implications during breast cancer progression and metastasis. Here, I discuss the mechanisms and the evidence underlying these diverse roles for autophagy in cancer and speculate on specific circumstances in which autophagy can be most effectively targeted for breast cancer treatment.

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    • "Therefore, the possibility of activating alternative cell death pathways holds promise . In recent years, studies have reported the activation of autophagy in tumor cells following anticancer therapies such as radiation and chemotherapy (Paglin et al., 2001; Wilson et al., 2011; Debnath, 2011) as well as nonconventional therapies (Gorka et al., 2005). "
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    DESCRIPTION: Autophagy is a natural self-degradative process by which cells eliminate misfolded proteins and damaged organelles. Autophagy has been shown to have multiple functions in tumor cells that may be dependent on the tumor type and the treatment conditions. Autophagy can have a cytoprotective role and be thought of as a survival mechanism or be cytotoxic in nature and mediate cell death. Radiation, one of the primary treatments for many different types of cancer, almost uniformly promotes autophagy in tumor cells. While autophagy produced in response to radiation is often considered to be cytoprotective, radiation-induced autophagy has also been shown to mediate susceptibility to radiation. This review addresses the complexity of autophagy in response to radiation treatment in three different cancer models, specifically lung cancer, breast cancer and glioblastoma. A deeper understanding of the different roles played by autophagy in response to radiation should facilitate the development of approaches for enhancing the therapeutic utility of radiation by providing strategies for combination treatment with unique radiosensitizers as well as preventing the initiation of strategies which are likely to attenuate the effectiveness of radiation therapy.
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    • "Autophagy also plays a role in various cancers such as breast cancer. This process has a “double-edged sword” role in cancer depending on the cell type, the context or the stage of tumor development [50], [51], [52]. As such, we wondered whether the involvement of QSOX1 in autophagy might explain its function in tumor progression. "
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    ABSTRACT: The QSOX1 protein (Quiescin Sulfhydryl oxidase 1) catalyzes the formation of disulfide bonds and is involved in the folding and stability of proteins. More recently, QSOX1 has been associated with tumorigenesis and protection against cellular stress. It has been demonstrated in our laboratory that QSOX1 reduces proliferation, migration and invasion of breast cancer cells in vitro and reduces tumor growth in vivo. In addition, QSOX1 expression has been shown to be induced by oxidative or ER stress and to prevent cell death linked to these stressors. Given the function of QSOX1 in these two processes, which have been previously linked to autophagy, we wondered whether QSOX1 might be regulated by autophagy inducers and play a role in this catabolic process. To answer this question, we used in vitro models of breast cancer cells in which QSOX1 was overexpressed (MCF-7) or extinguished (MDA-MB-231). We first showed that QSOX1 expression is induced following amino acid starvation and maintains cellular homeostasis. Our results also indicated that QSOX1 inhibits autophagy through the inhibition of autophagosome/lysosome fusion. Moreover, we demonstrated that inhibitors of autophagy mimic the effect of QSOX1 on cell invasion, suggesting that its role in this process is linked to the autophagy pathway. Previously published data demonstrated that extinction of QSOX1 promotes tumor growth in NOG mice. In this study, we further demonstrated that QSOX1 null tumors present lower levels of the p62 protein. Altogether, our results demonstrate for the first time a role of QSOX1 in autophagy in breast cancer cells and tumors.
    PLoS ONE 01/2014; 9(1):e86641. DOI:10.1371/journal.pone.0086641 · 3.23 Impact Factor
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    • "Thus, the cytotoxic effect of papuamine was caused by the induction of autophagy in MCF-7 cells. A growing number of functional studies support the use of autophagy regulation in combination with established therapies for breast cancer treatment for improved clinical outcome (28). Since the early days of autophagy research, the anti-estrogen tamoxifen has been known to be a potent inducer of autophagy in a variety of breast cancer cells (29). "
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    ABSTRACT: We previously reported that extracts of an Indonesian marine sponge Haliclona sp. showed potent cytotoxicity and the induction of apoptosis against human solid cancer cell lines. In this study, we examine the cytotoxic mechanism of the major chemical compound, papuamine, on MCF-7 human breast cancer cells. Papuamine at 5 µM did not show significant cytotoxic effects after incubation for 24 h, but autophagosome vesicular formation was apparent. At 10 µM of papuamine, significant reduction in cell survival was observed at 12 h, and increases in autophagy at this concentration were time-dependent and apparent before the appearance of cytotoxic effects. Both the release of cytochrome c to the cytosol and increase in Bax in the mitochondrial fraction were found to be concentration-dependent. Moreover, mitochondrial membrane potential shows concentration- and time-dependent decreases with exposure to papuamine. The release of cytochrome c has been shown to be accompanied by an increase in JNK activation. 3-Methyladenine (MA), a classical autophagy inhibitor showed increased JNK activation by exposure to papuamine. In conclusion, our results indicate that papuamine causes earlier onset autophagy and delayed reduction of cell survival through mitochondrial damage and JNK activation in MCF-7 cells.
    International Journal of Oncology 09/2013; 43(5). DOI:10.3892/ijo.2013.2093 · 3.03 Impact Factor
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