Expression of BNIP3 in invasive breast cancer: correlations with the hypoxic response and clinicopathological features

Koop, Esther; Laar, Theo van; Wichen, D.F. van; Weger, Roel A. de; Wall, Elsken van der; Diest, Paul J. van

doi:10.1186/1471-2407-9-175

Cited by 52 publications

(45 citation statements)

References 32 publications

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“…Therefore, BNIP3 acts as a tumor suppressor in mouse models (Manka et al 2005;Chourasia et al 2015b). Loss of BNIP3 is observed in triple-negative breast cancer (Koop et al 2009;van Diest et al 2010;Chourasia et al 2015b), and mice carrying a targeted deletion of BNIP3 sustain increased rates of tumor growth, acquire invasiveness, and increase spontaneous metastasis (Chourasia et al 2015b). Tumors in these mice have increased mitochondrial mass but reduced mitochondrial respiration and metabolite uptake.…”

Section: Regulation Of Core Autophagy Genes and Cargo Receptors In Camentioning

confidence: 99%

Recent insights into the function of autophagy in cancer

2016

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Macroautophagy (referred to here as autophagy) is induced by starvation to capture and degrade intracellular proteins and organelles in lysosomes, which recycles intracellular components to sustain metabolism and survival. Autophagy also plays a major homeostatic role in controlling protein and organelle quality and quantity. Dysfunctional autophagy contributes to many diseases. In cancer, autophagy can be neutral, tumor-suppressive, or tumorpromoting in different contexts. Large-scale genomic analysis of human cancers indicates that the loss or mutation of core autophagy genes is uncommon, whereas oncogenic events that activate autophagy and lysosomal biogenesis have been identified. Autophagic flux, however, is difficult to measure in human tumor samples, making functional assessment of autophagy problematic in a clinical setting. Autophagy impacts cellular metabolism, the proteome, and organelle numbers and quality, which alter cell functions in diverse ways. Moreover, autophagy influences the interaction between the tumor and the host by promoting stress adaptation and suppressing activation of innate and adaptive immune responses. Additionally, autophagy can promote a cross-talk between the tumor and the stroma, which can support tumor growth, particularly in a nutrient-limited microenvironment. Thus, the role of autophagy in cancer is determined by nutrient availability, microenvironment stress, and the presence of an immune system. Here we discuss recent developments in the role of autophagy in cancer, in particular how autophagy can promote cancer through suppressing p53 and preventing energy crisis, cell death, senescence, and an anti-tumor immune response.The core autophagy machinery is encoded by autophagyrelated (ATG) genes, of which there are now >30 (Ktistakis and Tooze 2016). These genes and their protein products are regulated by numerous upstream signals, including nutrient availability, stressors, defective organelles, and pathogenic conditions. ATG gene products control the formation of the hallmark double-membrane vesicle, the autophagosome. Other genes encode cargo receptors that direct the cargo to the forming autophagosome. Control of the trafficking machinery then orchestrates fusion of the cargo-laden autophagosomes with lysosomes. Degradative enzymes, contributed by lysosomes, break down the cargo, and the products are exported into the cytoplasm, where they are recycled into metabolic and biosynthetic pathways (Rabinowitz and White 2010;Guo et al. 2016). Under normal nutrient conditions, autophagy functions at a constitutive, low basal level to maintain protein and organelle quality, quantity, and functionality. The ATG genes and autophagy are dramatically induced by starvation and other stressors, which enable cellular and organismal survival. Up-regulation of autophagy is a means to survive nutrient stress, which is conserved from yeast to mammals. More recently, there is a growing appreciation of the role played by ATG genes in modulating intracellular trafficking, endocytosis, exoc...

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Section: Regulation Of Core Autophagy Genes and Cargo Receptors In Camentioning

confidence: 99%

Recent insights into the function of autophagy in cancer

2016

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“…There are reports of BNIP3 and NIX deregulation in cancer, including pancreas, prostate, colon, liver, breast, lung, brain, and blood (10,11,27,33,49,69,70,79,93,94). Deregulation of BNIP3 is correlated with tumor grade, metastases, and poor prognosis.…”

Section: Bnip3 and Nix In Human Diseasementioning

confidence: 99%

Mechanisms and Biology of B-Cell Leukemia/Lymphoma 2/Adenovirus E1B Interacting Protein 3 and Nip-Like Protein X

Zhang

Ney

2011

Antioxidants & Redox Signaling

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B-cell leukemia/lymphoma 2 (BCL-2)/adenovirus E1B interacting protein 3 (BNIP3) and Nip-like protein X (NIX) are atypical BCL-2 homology domain 3-only proteins involved in cell death, autophagy, and programmed mitochondrial clearance. BNIP3 and NIX cause cell death by targeting mitochondria, directly through BCL-2-associated X protein-or BCL-2-antagonist/killer-dependent mechanisms, or indirectly through an effect on calcium stores in the endoplasmic reticulum. BNIP3 and NIX also induce autophagy through an effect on mitochondrial reactive oxygen species production, or by releasing Beclin 1 from inhibitory interactions with antiapoptotic BCL-2 family proteins. BNIP3 downregulates mitochondrial mass in hypoxic cells, whereas NIX is required for mitochondrial elimination during erythroid development. BNIP3 and NIX have an emerging role in human health. Cell death mediated by BNIP3 and NIX is implicated in heart disease and ischemic injury. Cancer progression is linked to loss of the prodeath function of BNIP3, but also to induction of its prosurvival activity. Finally, BNIP3 and NIX are implicated in mitochondrial quality control, which is important in aging and degenerative disease. Elucidation of the mechanisms by which BNIP3 and NIX regulate cell death, autophagy, and mitochondrial clearance may lead to treatments for these conditions.

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“…Although BNIP3 methylation detected with probe 157 is associated with lower BNIP3 expression at the RNA level, its low level suggests that methylation does not seem to be a major explanation for the differential BNIP3 expression in invasive breast cancer previously described [9].…”

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confidence: 95%

“…Low or absent expression has been described in several human tumors, resulting in poor prognosis [1]. We previously reported that BNIP3 expression is lost in a significant portion of invasive breast cancers, which was correlated with poor prognostic features such as positive lymph node status and high proliferation [9]. Since DNA promoter hypermethylation ("methylation") is a common mechanism to silence gene expression, contributing to tumor-progression and invasion, we further studied the relation between BNIP3 methylation and gene expression by RNA in situ hybridization (ISH) in invasive breast cancer.…”

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confidence: 99%