Low Levels of<i>BNIP3</i>Promoter Hypermethylation in Invasive Breast Cancer

Diest, Paul J. van; Suijkerbuijk, Karijn; Koop, Esther; Weger, Roel A. de; Wall, Elsken van der

doi:10.1155/2010/852197

Cited by 7 publications

(4 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In pancreatic cancer in particular, inactivation of BNIP3 was associated with chemoresistance and poor prognosis . However, epigenetic silencing is not the likely mechanism of BNIP3 inactivation in human breast cancer .…”

Section: Resultsmentioning

confidence: 99%

Mitophagy defects arising from BNip3 loss promote mammary tumor progression to metastasis

et al. 2015

View full text Add to dashboard Cite

BNip3 is a hypoxia-inducible protein that targets mitochondria for autophagosomal degradation. We report a novel tumor suppressor role for BNip3 in a clinically relevant mouse model of mammary tumorigenesis. BNip3 delays primary mammary tumor growth and progression by preventing the accumulation of dysfunctional mitochondria and resultant excess ROS production. In the absence of BNip3, mammary tumor cells are unable to reduce mitochondrial mass effectively and elevated mitochondrial ROS increases the expression of Hif-1a and Hif target genes, including those involved in glycolysis and angiogenesis-two processes that are also markedly increased in BNip3-null tumors. Glycolysis inhibition attenuates the growth of BNip3-null tumor cells, revealing an increased dependence on autophagy for survival. We also demonstrate that BNIP3 deletion can be used as a prognostic marker of tumor progression to metastasis in human triple-negative breast cancer (TNBC). These studies show that mitochondrial dysfunctioncaused by defects in mitophagy-can promote the Warburg effect and tumor progression, and suggest better approaches to stratifying TNBC for treatment.

show abstract

Section: Resultsmentioning

confidence: 99%

Mitophagy defects arising from BNip3 loss promote mammary tumor progression to metastasis

et al. 2015

View full text Add to dashboard Cite

show abstract

“…In pancreatic adenocarcinoma and colorectal cancer Bnip3 transcription is prevented by hypermethylation of the Bnip3 promoter [40, 41]. In glioblastoma and non-small lung carcinomas Bnip3 protein is sequestered in the nuclei where it may actually block apoptosis by suppressing transcription of the apoptosis-inducing factor (AIF) and death receptor 5 (DR5) genes [42, 43].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the vacuolar ATPase induces Bnip3-dependent death of cancer cells and a reduction in tumor burden and metastasis

2013

View full text Add to dashboard Cite

The pro-apoptotic protein Bnip3 is induced by hypoxia and is present in the core regions of most solid tumors. Bnip3 induces programmed necrosis by an intrinsic caspase independent mitochondrial pathway. Many tumor cells have evolved pathways to evade Bnip3-mediated death attesting to the physiological relevance of the survival threat imposed by Bnip3. We have reported that acidosis can trigger the Bnip3 death pathway in hypoxic cells therefore we hypothesized that manipulation of intracellular pH by pharmacological inhibition of the vacuolar (v)ATPase proton pump, a significant pH control pathway, may activate Bnip3 and promote death of hypoxic cells within the tumor. Here we confirm that bafilomycin A1 (BafA1), a selective vATPase inhibitor, significantly increased death of breast cancer cells in a hypoxia and Bnip3-dependent manner and significantly reduced tumor growth in MCF7 and MDA-MB-231 mouse xenografts. Combined treatment of cells with BafA1 and the ERK1/2 inhibitor U0126 further augmented cell death. Combined treatment of mice containing MDA-MB-231 xenografts with BafA1 and the ERK1/2 inhibitor sorafenib was superior to either treatment alone and supported tumor regression. BafA1 and sorafenib treatments alone reduced MDA-MB-231 cell metastasis and again the combination was significantly more effective than either treatment alone and was without apparent side effects. These results present a novel mechanism to destroy hypoxic tumor cells that may help reverse the resistance of hypoxic tumors to radiation and chemotherapy and perhaps target tumor stem cells.

show abstract

“…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

View full text Add to dashboard Cite

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...

show abstract

Low Levels ofBNIP3Promoter Hypermethylation in Invasive Breast Cancer

Cited by 7 publications

References 9 publications

Mitophagy defects arising from BNip3 loss promote mammary tumor progression to metastasis

Mitophagy defects arising from BNip3 loss promote mammary tumor progression to metastasis

Inhibition of the vacuolar ATPase induces Bnip3-dependent death of cancer cells and a reduction in tumor burden and metastasis

Recent insights into the function of autophagy in cancer

Contact Info

Product

Resources

About