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Cannibalism, cell survival, and endocrine resistance in breast cancer

DOI: 10.1186/bcr2870

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Approximately 70% of newly diagnosed breast cancers express detectable levels of estrogen receptor alpha (ERα). Patients with these tumors generally receive an endocrine-based intervention, usually in the form of an aromatase inhibitor or antiestrogen. While these interventions are associated with a significant increase in overall survival [1], many ERα-positive breast cancers recur.Breast cancer cells often respond to endocrine therapies by altering the expression of a subset of estrogen-responsive and nonresponsive genes and inducing autophagy [2-7]. Autophagy is a lysosomal self-digestion pathway, where selected subcellular components are first segregated into double membrane-bound structures called autophagosomes [8]. Subsequent fusion with lysosomes forms autolysosomes, which enables the materials sequestered therein to be digested by lysosomal hydrolases. Three primary forms of autophagy have been described: macroautophagy, microautophagy, and chaperone-mediated autophagy. The comments in this viewpoint relate primarily to macroautophagy.Autophagy can be prodeath or prosurvival and reflects an attempt by stressed cells to eliminate damaged or other organelles and recover the energy stored in their macromolecules to restore metabolic homeostasis. Autophagy can result from activation of the unfolded protein response (UPR) [9] in response to the metabolic stress of endocrine therapies [4]. In endocrine manipulated cells, prosurvival autophagy signaling is driven at least partly by UPR activation of the unconventional splicing of the estrogen-responsive XBP1 mRNA [3,10] and, downstream, increased expression of BCL2 family members including BCL2 and BCLW (BCL2L2) [11]. Prodeath signaling can involve induction of a caspasedependent apoptotic cell death (programmed cell death 1) [12] when there is adequate energy, and an autophagy-associated necrotic cell death that is probably energy independent [11]. An autophagic cell death, often referred to as programmed cell de

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