Dataset Information

Effect of Genetic Polymorphisms and Long-Term Tobacco Exposure on the Risk of Breast Cancer.

ABSTRACT: Tobacco smoke contains many potentially harmful compounds that may act differently and at different stages in breast cancer development. The focus of this work was to assess the possible role of cigarette smoking (status, dose, duration or age at initiation) and polymorphisms in genes coding for enzymes involved in tobacco carcinogen metabolism (CYP1A1, CYP2A6) or in DNA repair (XRCC1, APEX1, XRCC3 and XPD) in breast cancer development.We designed a case control study with 297 patients, 217 histologically verified breast cancers (141 smokers and 76 non-smokers) and 80 healthy smokers in a cohort of Spanish women.We found an association between smoking status and early age at diagnosis of breast cancer. Among smokers, invasive carcinoma subtype incidence increased with intensity and duration of smoking (all Ptrend < 0.05). When smokers were stratified by smoking duration, we only observed differences in long-term smokers, and the CYP1A1 Ile462Ile genotype was associated with increased risk of breast cancer (OR = 7.12 (1.98-25.59)).Our results support the main effect of CYP1A1 in estrogenic metabolism rather than in tobacco carcinogen activation in breast cancer patients and also confirmed the hypothesis that CYP1A1 Ile462Val, in association with long periods of active smoking, could be a breast cancer risk factor.

SUBMITTER: Verde Z

PROVIDER: S-EPMC5085757 | biostudies-other | 2016 Oct

REPOSITORIES: biostudies-other

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Effect of Genetic Polymorphisms and Long-Term Tobacco Exposure on the Risk of Breast Cancer.

Verde Zoraida Z Santiago Catalina C Chicharro Luis Miguel LM Reinoso-Barbero Luis L Tejerina Alejandro A Bandrés Fernando F Gómez-Gallego Félix F

International journal of molecular sciences 20161014 10

<h4>Introduction</h4>Tobacco smoke contains many potentially harmful compounds that may act differently and at different stages in breast cancer development. The focus of this work was to assess the possible role of cigarette smoking (status, dose, duration or age at initiation) and polymorphisms in genes coding for enzymes involved in tobacco carcinogen metabolism (CYP1A1, CYP2A6) or in DNA repair (XRCC1, APEX1, XRCC3 and XPD) in breast cancer developme ...[more]

PMID: 27754415

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Project description:ImportanceAccurate long-term breast cancer risk assessment for women attending routine screening could help reduce the disease burden and intervention-associated harms by personalizing screening recommendations and preventive interventions.ObjectiveTo report the accuracy of risk assessment for breast cancer during a period of 19 years.Design, setting, and participantsThis cohort study of the Kaiser Permanente Washington breast imaging registry included women without previous breast cancer, aged 40 to 73 years, who attended screening from January 1, 1996, through December 31, 2013. Follow-up was completed on December 31, 2014, and data were analyzed from March 2, 2016, through November 13, 2017.ExposuresRisk factors from a questionnaire and breast density from the Breast Imaging and Reporting Data System at entry; primary risk was assessed using the Tyrer-Cuzick model.Main outcomes and measuresIncidence of invasive breast cancer was estimated with and without breast density. Follow-up began 6 months after the entry mammogram and extended to the earliest diagnosis of invasive breast cancer, censoring at 75 years of age, 2014, diagnosis of ductal carcinoma in situ, death, or health plan disenrollment. Observed divided by expected (O/E) numbers of cancer cases were compared using exact Poisson 95% CIs. Hazard ratios for the top decile of 10-year risk relative to the middle 80% of the study population were estimated. Constancy of relative risk calibration during follow-up was tested using a time-dependent proportional hazards effect.ResultsIn this cohort study of 132 139 women (median age at entry, 50 years; interquartile range, 44-58 years), 2699 invasive breast cancers were subsequently diagnosed after a median 5.2 years of follow-up (interquartile range, 2.4-11.1 years; maximum follow-up, 19 years; annual incidence rate [IR] per 1000 women, 2.9). Observed number of cancer diagnoses was close to the expected number (O/E for the Tyrer-Cuzick model, 1.02 [95% CI, 0.98-1.06]; O/E for the Tyrer-Cuzick model with density, 0.98 [95% CI, 0.94-1.02]). The Tyrer-Cuzick model estimated 2554 women (1.9%) to be at high risk (10-year risk of ?8%), of whom 147 subsequently developed invasive breast cancer (O/E, 0.79; 95% CI, 0.67-0.93; IR per 1000 women, 8.7). The Tyrer-Cuzick model with density estimated more women to be at high risk (4645 [3.5%]; 273 cancers [10.1%]; O/E, 0.78; 95% CI, 0.69-0.88; IR per 1000 women, 9.2). The hazard ratio for the highest risk decile compared with the middle 80% was 2.22 (95% CI, 2.02-2.45) for the Tyrer-Cuzick model and 2.55 (95% CI, 2.33-2.80) for the Tyrer-Cuzick model with density. Little evidence was found for a decrease in relative risk calibration throughout follow-up for the Tyrer-Cuzick model (age-adjusted slope, -0.003; 95% CI, -0.018 to 0.012) or the Tyrer-Cuzick model with density (age-adjusted slope, -0.008; 95% CI, -0.020 to 0.004).Conclusions and relevanceBreast cancer risk assessment combining classic risk factors with mammographic density may provide useful data for 10 years or more and could be used to guide long-term, systematic, risk-adapted screening and prevention strategies.

Project description:Alcohol consumption is a risk factor for breast cancer. Little is known regarding the mechanism, although it is assumed that acetaldehyde or estrogen mediated pathways play a role. We previously showed that long-term exposure to 2.5 mM ethanol (blood alcohol ~0.012%) of MCF-12A, a human normal epithelial breast cell line, induced epithelial mesenchymal transition (EMT) and oncogenic transformation. In this study, we investigated in the human breast cancer cell line MCF-7, whether a similar exposure to ethanol at concentrations ranging up to peak blood levels in heavy drinkers would increase malignant progression. Short-term (1-week) incubation to ethanol at as low as 1-5 mM (corresponding to blood alcohol concentration of ~0.0048-0.024%) upregulated the stem cell related proteins Oct4 and Nanog, but they were reduced after exposure at 25 mM. Long-term (4-week) exposure to 25 mM ethanol upregulated the Oct4 and Nanog proteins, as well as the malignancy marker Ceacam6. DNA microarray analysis in cells exposed for 1 week showed upregulated expression of metallothionein genes, particularly MT1X. Long-term exposure upregulated expression of some malignancy related genes (STEAP4, SERPINA3, SAMD9, GDF15, KRT15, ITGB6, TP63, and PGR, as well as the CEACAM, interferon related, and HLA gene families). Some of these findings were validated by RT-PCR. A similar treatment also modulated numerous microRNAs (miRs) including one regulator of Oct4 as well as miRs involved in oncogenesis and/or malignancy, with only a few estrogen-induced miRs. Long-term 25 mM ethanol also induced a 5.6-fold upregulation of anchorage-independent growth, an indicator of malignant-like features. Exposure to acetaldehyde resulted in little or no effect comparable to that of ethanol. The previously shown alcohol induction of oncogenic transformation of normal breast cells is now complemented by the current results suggesting alcohol's potential involvement in malignant progression of breast cancer.

Dataset Information

Effect of Genetic Polymorphisms and Long-Term Tobacco Exposure on the Risk of Breast Cancer.

Publications

Effect of Genetic Polymorphisms and Long-Term Tobacco Exposure on the Risk of Breast Cancer.

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