NAD(P)H:quinone oxidoreductase 1 NQO1*2 genotype (P187S) is a strong prognostic and predictive factor in breast cancer

Fagerholm, Rainer; Hofstetter, Barbara; Tommiska, Johanna; Aaltonen, Kirsimari; Vrtěl, Radek; Syrjäkoski, Kirsi; Kallioniemi, Anne; Kilpivaara, Outi; Mannermaa, Arto; Kosma, Veli‐Matti; Uusitupa, Matti; Eskelinen, Matti; Kataja, Vesa; Aittomäki, Kristiina; Smitten, Karl von; Heikkilä, Päivi; Lukáš, Jiří; Holli, Kaija; Bártková, Jiřina; Blomqvist, Carl; Bártek, Jiří; Nevanlinna, Heli

doi:10.1038/ng.155

Cited by 181 publications

(187 citation statements)

References 42 publications

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“…70 A recent paper reports that this polymorphism is a strong prognostic and predictive factor in breast cancer. 71 This paper shows that the NQO1 polymorphism leads to lower basal levels of p53, and also has an effect on the accumulation of p53 in response to epirubicin, in addition to p53-independent effects. These studies support the hypothesis that ubiquitin-independent degradation of p53 is a significant process and NQO1, an enzyme that inhibits this process, is important to keep the tumor suppressor function of p53 effective.…”

Section: Relevance To Cancermentioning

confidence: 80%

Ubiquitin-independent p53 proteasomal degradation

2009

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The mechanism of p53 proteasomal degradation through polyubiquitination is well characterized. The basic assumption behind this mechanism is that p53 is inherently stable unless sensitized to degradation by polyubiquitination. However, a number of studies provide evidence for p53 to be naturally unstable. Consistent with this attribute is the fact that both p53 N-and C-termini are intrinsically unstructured. Recent findings provide evidence for p53 to be degraded by the 20S proteasome by default unless it escapes this process. A number of mechanisms were demonstrated and proposed to play a role in rescuing p53 from default degradation. These mechanisms, their biological implications, and relevance to cancer are reviewed in this article.

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Section: Relevance To Cancermentioning

confidence: 80%

Ubiquitin-independent p53 proteasomal degradation

2009

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“…15 Fagerholm et al proposed that NQO1 influences the outcome of epirubicin treatment through at least three mechanisms: the TP53 and TNF-NF-kB pathways and direct detoxification of reactive oxygen species. 15 Our study at both mRNA and protein levels did not find additional evidence about the mechanism of NQO1-TP53 association. 16 Thus, more complex mechanism may be behind the reported association.…”

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confidence: 99%

Association of superoxide dismutases and NAD(P)H quinone oxidoreductases with prognosis of patients with breast carcinomas

Hubackova

Václavíková

Ehrlichová

et al. 2011

Intl Journal of Cancer

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Associations of transcript levels of oxidative stress-modifying genes SOD2, SOD3, NQO1 and NQO2 and their functional single nucleotide polymorphisms (SNPs) rs4880, rs1799895, rs2536512, rs699473, rs1800566 and rs1143684 with prognosis of breast cancer patients were studied. SNPs were assessed by allelic discrimination in a cohort of 321 breast cancer patients from the Czech Republic. Transcript levels were determined by real-time polymerase chain reaction (PCR) with absolute quantification in tumor and adjacent non-neoplastic control tissues. Both genotypes and transcript levels were then compared with available clinical data on patients. Patients carrying low activity allele Leu in NQO2 rs1143684 had a greater incidence of stage 0 or I disease (i.e., better prognosis) than patients with the Phe/Phe genotype. This association was more evident in patients without expression of progesterone receptors (p 5 0.031). Patients carrying the Thr allele in SOD3 rs2536512 SNP had a significantly greater incidence of tumors expressing estrogen receptors than patients carrying the Ala/Ala genotype (p 5 0.007). SOD3 transcript level was significantly higher in grade 1 or 2 tumors than in grade 3 tumors (p 5 0.006). Patients carrying T allele in SOD3 rs699473 SNP had significantly poorer progression-free survival (PFS) than patients carrying the CC genotype (p 5 0.038). The same applied to the subgroup of patients treated by hormonal regimens (p 5 0.021). Patients carrying the high activity Ala/Ala genotype in SOD2 (rs4880) had significantly poorer PFS than Val allele carriers in the group treated by cyclophosphamide but not hormonal regimens (p 5 0.004). Our results suggest that NQO2, SOD2 and SOD3 may significantly modify prognosis of breast cancer patients and that their significance should be further characterized.Breast cancer is the most common cancer in women. In 2008, about 1,383,523 new cases of invasive breast cancer were diagnosed worldwide. 1 The necessity of treating such a large number of patients calls for efficient tools that can be used for subgrouping patients according to estimated prognosis. A different spectrum of treatment modalities with diverse mechanisms of action and adverse effects could then be offered to various prognostic groups. Besides well-established classical prognostic factors such as tumor size, nodal status, grading and expression of hormonal receptors, numerous biological molecules are under investigation as potential prognostic biomarkers in breast carcinomas.Excess of oxidative stress, mediated by reactive oxygen species, may cause cellular deregulation leading to cell apoptosis, 2 proliferation or tumor promotion. 3 Alkylation and topoisomerase poisoning present the major mechanisms of action of cyclophosphamide and anthracyclines, respectively. Oxidative stress represents an additional cytotoxic mechanism. 4,5 One of the initial molecules of oxidative stress, superoxide anion radical, is formed by the univalent reduction of triplet-state molecular oxygen. This process is mediated by e...

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“…The association between common germline genetic variation and breast cancer-specific survival has been examined in many candidate gene studies (8)(9)(10)(11)(12)(13)(14)(15)(16). These studies have identified numerous single nucleotide polymorphisms (SNPs) possibly associated with outcome, but none have been conclusively replicated in further studies.…”

Section: Resultsmentioning

confidence: 99%