Expression of hypoxia-inducible factor 1 alpha and its downstream targets in fibroepithelial tumors of the breast

Kuijper, Arno; Groep, Petra van der; Wall, Elsken van der; Diest, Paul J. van

doi:10.1186/bcr1296

Cited by 26 publications

(21 citation statements)

References 48 publications

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“…These markers include ATG16L1 and the cathepsins (K and D) for autophagy, as well as carbonic anhydrase IX (CAIX) and HIF1-a for oxidative stress. [49][50][51][52][53][54][55][56] Furthermore, re-analysis of the published transcriptional profiles 15 of laser-captured tumor stroma, isolated from human breast cancers, reveals strong evidence for the enrichment of autophagy genes, lysosomal markers, as well as indicators of oxidative stress (such as peroxisomes), which were associated with tumor recurrence and metastasis. 16,30 These tumor stroma transcriptional profiles also showed significant overlap with the transcriptional profiles of Cav-1 (-/-) null stromal cells, 16,30,31 and Alzheimer disease brain (known to be associated with oxidative stress).…”

Section: Methodsmentioning

confidence: 99%

Molecular profiling of a lethal tumor microenvironment, as defined by stromal caveolin-1 status in breast cancers

Witkiewicz¹,

Kline²,

Queenan³

et al. 2011

Cell Cycle

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Breast cancer progression and metastasis are driven by complex and reciprocal interactions, between epithelial cancer cells and their surrounding stromal microenvironment. We have previously shown that a loss of stromal Cav-1 expression is associated with an increased risk of early tumor recurrence, metastasis and decreased overall survival. To identify and characterize the signaling pathways that are activated in Cav-1 negative tumor stroma, we performed gene expression profiling using laser microdissected breast cancer-associated stroma. Tumor stroma was laser capture microdissected from 4 cases showing high stromal Cav-1 expression and 7 cases with loss of stromal Cav-1. Briefly, we identified 238 gene transcripts that were upregulated and 232 gene transcripts that were downregulated in the stroma of tumors showing a loss of Cav-1 expression (p ≤ 0.01 and fold-change ≥ 1.5). Gene set enrichment analysis (GSEA) revealed "stemness," inflammation, DNA damage, aging, oxidative stress, hypoxia, autophagy and mitochondrial dysfunction in the tumor stroma of patients lacking stromal Cav-1. Our findings are consistent with the recently proposed "Reverse Warburg Effect" and the "Autophagic Tumor Stroma Model of Cancer Metabolism." In these two complementary models, cancer cells induce oxidative stress in adjacent stromal cells, which then forces these stromal fibroblasts to undergo autophagy/mitophagy and aerobic glycolysis. This, in turn, produces recycled nutrients (lactate, ketones and glutamine) to feed anabolic cancer cells, which are undergoing oxidative mitochondrial metabolism. Our results are also consistent with previous biomarker studies showing that the increased expression of known autophagy markers (such as ATG16L and the cathepsins) in the tumor stroma is specifically associated with metastatic tumor progression and/or poor clinical outcome.

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Section: Methodsmentioning

confidence: 99%

Molecular profiling of a lethal tumor microenvironment, as defined by stromal caveolin-1 status in breast cancers

Witkiewicz¹,

Kline²,

Queenan³

et al. 2011

Cell Cycle

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“…Autophagy induction in cancer cells may occur due to hypoxia (13,32), and it has been previously demonstrated that expression of hypoxiainducible factor 1α (HIF-1α) downstream targets is associated with a higher histologic grade in fibroepithelial tumors of the breast (33). In this scenario autophagy provides the nutrients needed for cancer survival and stabilization of HIF-1α allows for instance that higher grade phyllode tumors adapt to hypoxia (30).…”

Section: Discussionmentioning

confidence: 99%

Autophagy-associated proteins BAG3 and p62 in testicular cancer

et al. 2015

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Abstract. Testicular germ cell tumors (TGCT) represent the most common malignant tumor group in the age group of 20 to 40-years old men. The potentially curable effect of cytotoxic therapy in TGCT is mediated mainly by the induction of apoptosis. Autophagy has been discussed as an alternative mechanism of cell death but also of treatment resistance in various types of tumors. However, in TGCT the expression and role of core autophagy-associated factors is hitherto unknown. We designed the study in order to evaluate the potential role of autophagy-associated factors in the development and progression of testicular cancers. Eighty-four patients were assessed for autophagy (BAG3, p62) and apoptosis (cleaved caspase 3) markers using immunohistochemistry (IHC) on tissue microarrays. In addition, western blot analyses of frozen tissue of seminoma and non-seminoma were performed. Our findings show that BAG3 was significantly upregulated in seminoma as compared to non-seminoma but not to normal testicular tissue. No significant difference of p62 expression was detected between neoplastic and normal tissue or between seminoma and non-seminoma. BAG3 and p62 showed distinct loco-regional expression patterns in normal and neoplastic human testicular tissues. In contrast to the autophagic markers, apoptosis rate was significantly higher in testicular tumors as compared to normal testicular tissue, but not between different TGCT subtypes. The present study, for the first time, examined the expression of central autophagy proteins BAG3 and p62 in testicular cancer. Our findings imply that in general apoptosis but not autophagy induction differs between normal and neoplastic testis tissue. IntroductionThe effect of cytotoxic treatment in testicular tumors is mainly moderated by the induction of apoptosis (1). Due to the rapid response after exposure to chemotherapeutic agents an intact and effective apoptotic pathway in most testicular cancers is assumed (2). Nevertheless, various patients show complex clinical courses, including tumors with chemoresistence and thus lower apoptosis rates (3). Recent studies have shown that the elimination of cells may be also conducted using the alternative cell death pathway ʻautophagyʼ (4,5).Autophagy is an evolutionarily conserved, pervasive and multi-step ʻself-eatingʼ process, by which cytosolic material is sequestered in a double-lipid membrane, delivered to the lysosome for degradation and digested to provide energy and to build the foundation for cell-survival (6). While autophagy has for long been considered to be a bulk degradation process, recent discoveries show that it rather displays a sophisticated portfolio of selectivity provided by different molecular strategies such as the detection of several autophagy receptor proteins, including pacemaker molecules such as p62 (SQSTM1) and BCL2-associated athanogene 3 (BAG3) (7-9). To the best of our knowledge, no study has been published to date that examined the expression of the cohesive autophagy proteins BAG3 and p62 in testicular can...

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“…Several recent studies have demonstrated epidermal growth factor receptor (EGFR) overexpression in phyllodes tumors, with increasing expression accompanying increasing degree of malignancy [14,15]. Increased expression of stromal HIF-1 alpha [16], c-myc [11], CD10 [17], nitric-oxide synthase [18], heparan sulfate expression [19], Ki-67 [20], increased microvessel density, and VEGF [21,22] with increasing degree of malignancy have also been shown. Increased cell cycle deregulation has been observed with higher tumor grade [23].…”

Section: Introductionmentioning

confidence: 97%

Molecular classification of breast phyllodes tumors: validation of the histologic grading scheme and insights into malignant progression

Ang

Ooi

Thike

et al. 2010

Breast Cancer Res Treat

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Phyllodes tumors of the breast are rare fibroepithelial neoplasms with a potential for recurrence. Current histological classification is not always predictive of clinical behavior. The aim of this study was to identify genetic changes associated with the development of borderline and malignant phyllodes tumors in an Asian population, and to assess if genetic data supported the categorization of these tumors into the existing three grades of benign, borderline, and malignant. Expression profiling of 21 phyllodes tumors (6 benign, 10 borderline, 5 malignant) was performed using Affymetrix U133Plus 2.0 GeneChips(®). Gene expression among benign, borderline, and malignant tumors was compared and a 29 gene list was able to classify them according to their histologic grade. Among these 29 genes are those responsible for matrix formation, cell adhesion, epidermis formation, and cell proliferation. Comparative genomic microarray analysis showed that the most common chromosomal alteration associated with borderline and malignant tumors was 1q gain, and an increasing number of chromosomal changes was noted with increasing histological grade. Upregulation of HOXB13 was seen in malignant relative to borderline phyllodes tumors and further investigated by immunohistochemistry in a corresponding set of formalin-fixed, paraffin-embedded tumors. HOXB13 protein overexpression was found to be correlated with stromal hypercellularity and atypia (P = 0.03, P = 0.039, respectively) and may be implicated in the development of malignant phyllodes tumors.

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Expression of hypoxia-inducible factor 1 alpha and its downstream targets in fibroepithelial tumors of the breast

Cited by 26 publications

References 48 publications

Molecular profiling of a lethal tumor microenvironment, as defined by stromal caveolin-1 status in breast cancers

Molecular profiling of a lethal tumor microenvironment, as defined by stromal caveolin-1 status in breast cancers

Autophagy-associated proteins BAG3 and p62 in testicular cancer

Molecular classification of breast phyllodes tumors: validation of the histologic grading scheme and insights into malignant progression

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