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Rabstein S.,Ruhr University Bochum | Harth V.,University of Hamburg | Justenhoven C.,Bioscientia Center for Human Genetics | Pesch B.,Ruhr University Bochum | And 9 more authors.
Chronobiology International | Year: 2014

Objectives: The role of genetic variants and environmental factors in breast cancer etiology has been intensively studied in the last decades. Gene-environment interactions are now increasingly being investigated to gain more insights into the development of breast cancer, specific subtypes, and therapeutics. Recently, night shift work that involves circadian disruption has gained rising interest as a potential non-genetic breast cancer risk factor. Here, we analyzed genetic polymorphisms in genes of cellular clocks, melatonin biosynthesis and signaling and their association with breast cancer as well as gene-gene and gene-night work interactions in a German case-control study on breast cancer. Methods: GENICA is a population-based case-control study on breast cancer conducted in the Greater Region of Bonn. Associations between seven polymorphisms in circadian genes (CLOCK, NPAS2, ARTNL, PER2 and CRY2), genes of melatonin biosynthesis and signaling (AANAT and MTNR1B) and breast cancer were analyzed with conditional logistic regression models, adjusted for potential confounders for 1022 cases and 1014 controls. Detailed shift-work information was documented for 857 breast cancer cases and 892 controls. Gene-gene and gene-shiftwork interactions were analyzed using model-based multifactor dimensionality reduction (mbMDR). Results: For combined heterozygotes and rare homozygotes a slightly elevated breast cancer risk was found for rs8150 in gene AANAT (OR 1.17; 95% CI 1.01-1.36), and a reduced risk for rs3816358 in gene ARNTL (OR 0.82; 95% CI 0.69-0.97) in the complete study population. In the subgroup of shift workers, rare homozygotes for rs10462028 in the CLOCK gene had an elevated risk of breast cancer (OR for AA vs. GG: 3.53; 95% CI 1.09-11.42). Shift work and CLOCK gene interactions were observed in the two-way interaction analysis. In addition, gene-shiftwork interactions were detected for MTNR1B with NPAS2 and ARNTL. Conclusions: In conclusion, the results of our population-based case-control study support a putative role of the CLOCK gene in the development of breast cancer in shift workers. In addition, higher order interaction analyses suggest a potential relevance of MTNR1B with the key transcriptional factor NPAS2 with ARNTL. Hence, in the context of circadian disruption, multivariable models should be preferred that consider a wide range of polymorphisms, e.g. that may influence chronotype or light sensitivity. The investigation of these interactions in larger studies is needed. © 2014 Informa Healthcare USA, Inc. Source

Justenhoven C.,Robert Bosch GmbH | Justenhoven C.,University of Tubingen | Winter S.,Robert Bosch GmbH | Winter S.,University of Tubingen | And 9 more authors.
Cancer | Year: 2010

Background: CYP3A enzymes, due to their role in the metabolism of steroid hormones, are suggested to affect carcinogenesis of hormone-related cancers. The purpose of the present study was to evaluate the association between polymorphisms located in CYP3A43, breast cancer risk, and tumor characteristics. Methods: A 3-plex matrix-assisted laser desorption ionization time of flight mass spectrometry assay has been established for CYP3A43-74-delA (CYP3A43*2A), CYP3A43-1018-C>G (CYP3A43*3), and CYP3A43-1047-C>T (CYP3A43*1B) polymorphisms, and 1021 breast cancer cases and 1015 age-matched, population-based controls from the German GENICA collection have been genotyped. Results: No differences in genotype frequencies between cases and controls were observed, indicating that CYP3A43-74-delA is not associated with breast cancer risk. Subgroup analyses showed an association between the CYP3A43-74-delA allele and high-grade tumors (odds ratio, 1.74; 95% confidence interval, 1.14-2.65 [P =.010 and Ptrend =.012]). Conclusions: The data support the notion that the CYP3A43-74-delA variant may result in decreased protein and/or activity levels, and this may further lead to increased hormone levels to promote tumor cell growth and hinder differentiation. Cancer 2010. © 2010 American Cancer Society. CYP3A43 is involved in the metabolism of steroid hormones. The authors observed an association between the CYP3A43 74 del A polymorphism and grade of breast tumors (odds ratio, 1.74; Ptrend =.012). The variant allele may lead to increased steroid hormone levels promoting growth of tumor cells and hinder differentiation. Copyright © 2010 American Cancer Society. Source

Pesch B.,Ruhr University Bochum | Harth V.,Ruhr University Bochum | Rabstein S.,Ruhr University Bochum | Baisch C.,Evangelische Kliniken Bonn gGmbH | And 11 more authors.
Scandinavian Journal of Work, Environment and Health | Year: 2010

Objective: Some epidemiological and animal data indicate that night work might increase the risk for breast cancer. We have investigated the risk in a German population-based case-control study known as GENICA (Gene ENvironment Interaction and breast CAncer). Methods: The GENICA study involved interviews to assess shift work information in 857 breast cancer cases and 892 controls. We estimated risks of employment status and night shift characteristics using conditional logistic regression models, adjusting for potential confounders. Resampling and bootstrapping were applied to adjust the risk estimates for a potential selection bias. Results: Among 1749 women, 56 cases and 57 controls worked in night shifts for ≥1 year, usually in the healthcare sector (63.0% of controls). Female night workers were more frequently nulliparous and low-educated than day workers (28.6% versus 17.8% and 12.3% versus 9.2%, respectively). Fewer women in night work had ever used post-menopausal hormone therapy (35.7% versus 51.9%). Having ever done shift or night work was not associated with an elevated breast cancer risk when compared to women employed in day work only [odds ratio (OR) 0.96, 95% confidence interval (95% CI) 0.67-1.38 and OR 0.91, 95% CI 0.55-1.49, respectively). Women who reported >807 night shifts, the third quartile of the distribution among controls, experienced a breast cancer risk of 1.73 (95% CI 0.71-4.22). Night work for ≥20 years was associated with an OR of 2.48 (95% CI 0.62-9.99) based on 12 cases and 5 controls. Conclusions: Long-term night work was associated with a modestly, but not significantly, increased breast cancer risk, while having ever done night work was not. The precision of the results was limited by a low prevalence of night work in this study population. Source

Lang T.,Robert Bosch GmbH | Lang T.,University of Tubingen | Justenhoven C.,Robert Bosch GmbH | Justenhoven C.,University of Tubingen | And 15 more authors.
Breast Cancer Research and Treatment | Year: 2011

Genetic polymorphisms of human ABC-transporter genes have been suggested to modulate breast cancer risk in the general population. In particular ABCC11 (MRP8), which is highly expressed in breast cancer tissue and involved in the efflux of conjugated estrogen metabolites such as estrone-3-sulfate and estradiol-17beta-glucuronide, has recently been proposed as a potential risk factor for female breast cancer. The wet earwax-associated G-allele of the c.538G>A polymorphism was associated with an increased risk for breast cancer in Japanese women. In contrast, no evidence for such an association could be observed in Caucasian women. We aimed to confirm/refute the association of the c.538G>A variant in ABCC11 with breast cancer risk and/or histo-pathological tumor characteristics in an independent population-based breast cancer case-control study from Germany comprising 1021 cases and 1015 age-matched controls. No association for allele and genotype frequencies of the 538G>A variant in ABCB11 with breast cancer risk was found. Our data suggest that the c.538G>A variation in ABCC11 does not contribute to breast carcinogenesis in women of European descent. © 2011 Springer Science+Business Media, LLC. Source

Justenhoven C.,Robert Bosch GmbH | Justenhoven C.,University of Tubingen | Schaeffeler E.,Robert Bosch GmbH | Schaeffeler E.,University of Tubingen | And 14 more authors.
Breast Cancer Research and Treatment | Year: 2011

Organic anion transporter polypeptides (OATPs, SLCOs) are involved in the uptake of conjugates steroid hormones such as estrone-3-sulfate. It has been suggested that the expression of OATPs in breast tissues could impact breast carcinogenesis and tumor pathology. The nuclear receptor pregnane X receptor (PXR) is involved in the regulation of SLCO1A2 expression. We investigated 31 variants located in PXR, SLCO1A2, SLCO1B1, SLCO1B3, and SLCO2B1 for an association with breast cancer risk and/or histo-pathological tumor characteristics. Polymorphisms were selected on the basis of a known or potential functional consequence and an allele frequency >2%. Genotyping was performed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry using the GENICA population-based breast cancer case-control collection comprising 1,021 cases and 1,015 age-matched controls. Statistical analysis was performed by SAS, and all tests were two-sided. None of the 31 analyzed transporter and PXR polymorphisms showed an association with breast cancer risk or tumor characteristics. Our data suggest that among the many known transporters common variations of PXR, SLCO1A2, SLCO1B1, SLCO1B3, and SLCO2B1 do not contribute to breast carcinogenesis. © 2010 Springer Science+Business Media, LLC. Source

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