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- Bartkova, Jirina, et al.
(author)
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Aberrations of the MRE11-RAD50-NBS1 DNA damage sensor complex in human breast cancer : MRE11 as a candidate familial cancer-predisposing gene
- 2008
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In: Molecular Oncology. - : Wiley. - 1574-7891. ; 2:4, s. 296-316
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Journal article (peer-reviewed)abstract
- The MRE11, RAD50, and NBS1 genes encode proteins of the MRE11-RAD50-NBS1 (MRN) complex critical for proper maintenance of genomic integrity and tumour suppression; however, the extent and impact of their cancer-predisposing defects, and potential clinical value remain to be determined. Here, we report that among a large series of approximately 1000 breast carcinomas, around 3%, 7% and 10% tumours showed aberrantly reduced protein expression for RAD50, MRE11 and NBS1, respectively. Such defects were more frequent among the ER/PR/ERBB2 triple-negative and higher-grade tumours, among familial (especially BRCA1/BRCA2-associated) rather than sporadic cases, and the NBS1 defects correlated with shorter patients' survival. The BRCA1-associated and ER/PR/ERBB2 triple-negative tumours also showed high incidence of constitutively active DNA damage signalling (gamma H2AX) and p53 aberrations. Sequencing the RAD50, MRE11 and NBS1 genes of 8 patients from non-BRCA1/2 breast cancer families whose tumours showed concomitant reduction/loss of all three MRN-complex proteins revealed two germline mutations in MRE11: a missense mutation R202G and a truncating mutation R633STOP (R633X). Gene transfer and protein analysis of cell culture models with mutant MRE11 implicated various destabilization patterns among the MRN complex proteins including NBS1, the abundance of which was restored by re-expression of wild-type MRE11. We propose that germline mutations qualify MRE11 as a novel candidate breast cancer susceptibility gene in a subset of non-BRCA1/2 families. Our data have implications for the concept of the DNA damage response as an intrinsic anti-cancer barrier, various components of which become inactivated during cancer progression and also represent the bulk of breast cancer susceptibility genes discovered to date.
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- Heikkinen, Päivi, et al.
(author)
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A 28-day toxicity study with highly purified PCB 180 in Sprague–Dawley rats
- 2008
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In: Toxicology Letters. - : Elsevier. ; , s. 205-
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Conference paper (other academic/artistic)abstract
- PCB 180 is a persistent and accumulative heptachlorinated non-dioxin-like polychlorinated biphenyl (NDL-PCB) abundantly present in food and the environment. Risk characterisation of NDL-PCBs has been confounded by the presence of highly potent dioxin-like (DL) impurities. We used therefore highly purified PCB 180 (DL impurities 2.7 ng TEqWHO/g PCB 180) for the 28-day toxicity study in adult rats. Groups of 5 males and 5 females were given total doses of 3, 10, 30, 100, 300, 1000 or 1700 mg/kg PCB 180 by gavage. Total dose was divided into 6 daily loading doses and 3 weekly maintenance doses. Bodyweight development was retarded at 1700 mg/kg during loading dosing, but recovered by the end of the study. Hepatic effects are reported separately (Roos et al., ibid.). Thyroid weight was increased in males. Plasma free T4 was dose-dependently decreased (maximally by 69% in males and 50% in females) in association with thyroid follicle depletion, but T3 was not affected. Increased thyroid follicle cell vacuolization is suggestive of thyroid activation. In males, vacuolization and extracellular deposits were observed in the frontal part of pituitary. Activation of adrenal cortex is demonstrated by vacuolization and hypertrophy observed in cells of zona fasciculata of the adrenal cortex. Erythrocyte parameters (red blood cell count, haematocrit, haemoglobin) were dose-dependently decreased in both genders. The results demonstrate a distinct toxicological profile of PCB 180 with some similarities with that of DL compounds, but clearly lower potency.Acknowledgement: Funded by the European Commission (ATHON, FOOD-CT-2005-022923
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- Heikkinen, Tuomas, et al.
(author)
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The breast cancer susceptibility mutation PALB2 1592delT is associated with an aggressive tumor phenotype
- 2009
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In: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 15:9, s. 3214-22
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Journal article (peer-reviewed)abstract
- PURPOSE: To determine the effect of the breast cancer susceptibility mutation PALB2 1592delT on tumor phenotype and patient survival. EXPERIMENTAL DESIGN: We defined the PALB2 mutation status in 947 familial and 1,274 sporadic breast cancer patients and 1,079 population controls, and compared tumor characteristics and survival in mutation carriers relative to other familial and sporadic cases and to 79 BRCA1 and 104 BRCA2 mutation carrier cases. RESULTS: The PALB2 1592delT mutation was found in 19 familial [2.0%; odds ratio, 11.03; 95% confidence interval (95% CI), 2.65-97.78; P < 0.0001] and eight sporadic patients (0.6%; odds ratio, 3.40; 95% CI, 0.68-32.95; P = 0.1207) compared with two (0.2%) control individuals. Tumors of the PALB2 mutation carriers presented triple negative (estrogen receptor negative/progesterone receptor negative/HER negative) phenotype more often (54.5%; P < 0.0001) than those of other familial (12.2%) or sporadic (9.4%) breast cancer patients. They were also more often of higher grade (P = 0.0027 and P = 0.0017, respectively) and had higher expression of Ki67 (P = 0.0004 and P = 0.0490, respectively). Carrying a PALB2 mutation was also associated with reduced survival, especially in familial cases (hazard ratio, 2.30; 95% CI, 1.01-5.24; P = 0.0466) and among familial patients with HER2-negative tumors (hazard ratio, 4.57; 95% CI, 1.96-10.64; P = 0.0004). Carrying a BRCA2 mutation was also found to be an independent predictor of poor survival at 10-year follow-up (P = 0.04). CONCLUSIONS: The PALB2 1592delT mutation has a strong effect on familial breast cancer risk. The tumors rising in patients carrying this mutation manifest a phenotype associated with aggressive disease. Our results also suggest a significant impact of carrying a BRCA2 mutation on long-term breast cancer survival.
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