The prolyl hydroxylase enzymes are positively associated with hypoxia-inducible factor-1α and vascular endothelial growth factor in human breast cancer and alter in response to primary systemic treatment with epirubicin and tamoxifen

Fox, Stephen B.; Generali, Daniele; Berruti, Alfredo; Brizzi, Maria Pia; Campo, Leticia; Bonardi, S; Bersiga, Alessandra; Allevi, Giovanni; Milani, Manuela; Aguggini, Sergio; Mele, Teresa; Dogliotti, Luigi; Bottini, Alberto; Harris, Adrian L.

doi:10.1186/bcr2825

Cited by 24 publications

(24 citation statements)

References 34 publications

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“…The study also alludes to the prognostic importance of oncogenic drivers on disease-specific survival. As targeted therapies directed against HIF1A and downstream targets emerge, [36][37][38] these observation may also have important therapeutic implications for identifying specific populations for screening and explaining treatment efficacy in familial male breast cancers.…”

Section: Resultsmentioning

confidence: 99%

Nuclear HIF1A expression is strongly prognostic in sporadic but not familial male breast cancer

et al. 2014

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Male breast cancer is poorly understood with a large proportion arising in the familial context particularly with the BRCA2 germline mutation. As phenotypic and genotypic differences between sporadic and familial male breast cancers have been noted, we investigated the importance of a hypoxic drive in these cancers as this pathway has been shown to be of importance in familial female breast cancer. Expression of two major hypoxiainduced proteins, the hypoxia-inducible factor-1a (HIF1A) and the carbonic anhydrase IX (CA9), examined within a large cohort including 61 familial (3 BRCA1, 28 BRCA2, 30 BRCAX) and 225 sporadic male breast cancers showed that 31% of all male breast cancers expressed either HIF1A (25%) and/or CA9 (8%) in the combined cohort. Expression of HIF1A correlated with an increased incidence of a second-major malignancy (P ¼ 0.04), histological tumor type (P ¼ 0.005) and basal phenotype (P ¼ 0.02). Expression of CA9 correlated with age (P ¼ 0.004) in sporadic cases and an increased tumor size (P ¼ 0.003). Expression of HIF1A was prognostic for disease-specific survival in sporadic male breast cancers (HR: 3.8, 95% CI: 1.5-9.8, P ¼ 0.006) but not within familial male breast cancer, whereas CA9 was only prognostic in familial male breast cancers (HR: 358.0, 95% CI: 9.3-13781.7, P ¼ 0.002) and not in sporadic male breast cancer. This study found that hypoxic drive is less prevalent in male breast cancer compared with female breast cancer, possibly due to a different breast microenvironment. The prognostic impact of HIF1A is greatest in sporadic male breast cancers with an alternate dominant mechanism for the oncogenic drivers suggested in high risk familial male breast cancers.

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Section: Resultsmentioning

confidence: 99%

Nuclear HIF1A expression is strongly prognostic in sporadic but not familial male breast cancer

et al. 2014

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“…Prolyl hydroxylases (PHD1, also known as EGLN2) is 1 of the 3 enzymes capable of hydroxylating the alpha subunit of HIF and results in polyubiquitinylation and proteasomal degradation of HIF (10). Several lines of evidence have indicated that EGLN2 is involved in development of multiple cancers (11)(12)(13)(14). Whether EGLN2 promotes or suppresses tumorigenesis depends on its cell and cancer type-specific expression (15).…”

Section: Introductionmentioning

confidence: 99%

An Insertion/Deletion Polymorphism within RERT-lncRNA Modulates Hepatocellular Carcinoma Risk

Zhu

Gao

et al. 2012

Cancer Research

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The Prolyl hydroxylase 1 (EGLN2) is known to affect tumorigenesis by regulating the degradation of hypoxiainducible factor. Polymorphisms in EGLN2 may facilitate cancer cell survival under hypoxic conditions and directly associate with cancer susceptibility. Here, we examined the contribution of a 4-bp insertion/deletion polymorphism (rs10680577) within the distal promoter of EGLN2 to the risk of hepatocelluar carcinoma (HCC) in Chinese populations. The contribution of rs10680577 to HCC risk was investigated in 623 HCC cases and 1,242 controls and replicated in an independent case-control study consisting of 444 HCC cases and 450 controls. Logistic regression analysis showed that the deletion allele of rs10680577 was significantly associated with increased risk for HCC occurrence in both case-control studies [OR ¼ 1.40; 95% confidence interval (CI) ¼ 1.18-1.66, P < 0.0001; OR ¼ 1.49; 95% CI ¼ 1.18-1.88, P ¼ 0.0007]. Such positive association was more pronounced in current smokers (OR ¼ 3.49, 95% CI ¼ 2.24-5.45) than nonsmokers (OR ¼ 1.24, 95% CI ¼ 1.03-1.50; heterogeneity P ¼ 0.0002). Genotype-phenotype correlation studies showed that the deletion allele was significantly correlated with higher expression of both EGLN2 and RERT-lncRNA [a long noncoding RNA whose sequence overlaps with Ras-related GTP-binding protein 4b (RAB4B) and EGLN2)] in vivo and in vitro. Furthermore, RERT-lncRNA expression was also significantly correlated with EGLN2 expression in vivo, consistent with in vitro gain-offunction study that showed overexpressing RERT-lncRNA upregulated EGLN2. Finally, in silico prediction suggested that the insertion allele could disrupt the structure of RERT-lncRNA. Taken together, our findings provided strong evidence for the hypothesis that rs10680577 contributes to hepatocarcinogenesis, possibly by affecting RERT-lncRNA structure and subsequently EGLN2 expression, making it a promising biomarker for early diagnosis of HCC. Cancer Res; 72(23); 6163-72. Ó2012 AACR.

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“…This complexity reflects not only the crucial role of HIF1 in maintaining oxygen homeostasis but also the need to safeguard against its inappropriate activation. Previous reports have linked the PHD3-HIF and SUMOylation pathways with pathologies such as cancer and ischemia (Cheng et al, 2006;Chen et al, 2011;Flotho and Melchior, 2013;Fox et al, 2011;Loinard et al, 2009;Mo et al, 2005;Silveirinha et al, 2013;Su et al, 2010;Wang and Banerjee, 2004;Xue et al, 2010). In light of these findings, there is a great interest in the development of drugs targeting these pathways.…”

Section: Discussionmentioning

confidence: 99%

PHD3-SUMO conjugation optimizes HIF1 repression independently of PHD3 catalytic activity

Núñez-O'Mara

Gerpe-Pita

Pozo

et al. 2014

Journal of Cell Science

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By controlling HIFa hydroxylation and stability, the prolyl hydroxylase domain (PHD)-containing proteins are essential to the maintenance of oxygen homeostasis; therefore these enzymes are tightly regulated. Small ubiquitin-like modifier (SUMO) is a 10-kDa protein readily conjugated to lysine residues of the targeted proteins in a process termed SUMOylation. In this study, we introduce SUMO conjugation as a novel regulator of PHD3 (also known as EGLN3). PHD3 SUMOylation occurs at a cluster of four lysines at the C-terminal end of the protein. Furthermore, PHD3 SUMOylation by SUMO2 or SUMO3 contributes to PHD3-mediated repression of HIF1-dependent transcriptional activity. Interestingly, PHD3-SUMO conjugation does not affect PHD3 hydroxylase activity or HIF1a stability, providing new evidence for a dual role of PHD3 in HIF1 regulation. Moreover, we show that hypoxia modulates PHD3-SUMO conjugation and that this modification inversely correlates with HIF1 activation. PHD3 SUMOylation highlights a new and additional layer of regulation that is likely required to fine-tune HIF function.

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The prolyl hydroxylase enzymes are positively associated with hypoxia-inducible factor-1α and vascular endothelial growth factor in human breast cancer and alter in response to primary systemic treatment with epirubicin and tamoxifen

Cited by 24 publications

References 34 publications

Nuclear HIF1A expression is strongly prognostic in sporadic but not familial male breast cancer

Nuclear HIF1A expression is strongly prognostic in sporadic but not familial male breast cancer

An Insertion/Deletion Polymorphism within RERT-lncRNA Modulates Hepatocellular Carcinoma Risk

PHD3-SUMO conjugation optimizes HIF1 repression independently of PHD3 catalytic activity

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