In this Danish Nationwide cohort of female nurses we found a positive association between active tobacco smoking and breast cancer incidence in women older than 44 years, with the highest risk in women who smoked heavily and for a long duration of time. The strongest risk was detected in parous women who smoked heavily before 1st childbirth.
Our results confirmed the association between active smoking and breast cancer incidence reported in almost all recent prospective cohort studies. [6,7,8,9,10,11,12,13] Albeit, the 27% increased breast cancer risk that we found in current as compared to never smokers, was stronger than the effects seen in any of the earlier prospective studies. In other previous studies the risk of breast cancer was reported to be increased by 24% in both the American Cancer Society’s Cancer Prevention Study II (CPS-II)  and the Women’s Health Initiative (WHI)  studies; by 19% in the Norwegian women ; by 15% in American retired women ; by 8% in American Black Women’s Health Study (BWHS) ; by 5% in American Nurses’ Health Study (NHS) ; and by 6% in the EPIC cohort.  We also found a strong effect of high smoking intensity, with a 32% increased risk of breast cancer risk in women smoking >20 pack-years; a risk comparable to 34% increased risk observed in Norwegian women smoking ≥16 pack-years,  but stronger than effects found in any other study. [6,7,8, 11, 13]
The strong effects of smoking observed in both, our and in the Norwegian cohorts (both that part of EPIC study  .and the other Norwegian cohorts ) may be explained by high prevalence, duration and intensity of smoking in these Nordic cohorts with 34% of the women being current smokers at the time of recruitment as compared with 13% in American nurses,  8% in the American CPS-II study,  and 6% in the WHI study.  The average number of current smokers at the time of recruitment for the European countries in the EPIC study was 20%.  Furthermore, as we did not have data on passive smoking, our estimates for smoking are likely underestimated, as the EPIC study found that excluding passive smokers from the reference group led to higher risk estimates for active smoking. 
Notably, no association between smoking and breast cancer was found (current vs. never: 1.05; 0.72–1.54; former vs. never: 1.00; 0.68–1.47) in the Danish Diet, Cancer and Health cohort, which formed the Danish part of the EPIC study.  A possible reason for the difference between our results and those from Danish EPIC cohort could be that the women in the cohorts came from different birth cohorts. In the Danish EPIC cohort, the majority of women were born before 1944, and only 10% were born in 1945–1950. In the Danish Nurse Cohort, half of the women were born in 1945–1955 (Table 2). These younger birth cohorts started smoking earlier and were able to accumulate more years of smoking before the 1st childbirth than the older birth cohorts: on average 7.8 years as compared to 5.3 years (Table 2). The oldest generations in the Danish Nurse Cohort furthermore included a high proportion of nulliparous women; 27% for nurses born in 1990–1934 (Table 2), reflecting that before the Second World War Danish nurses were mostly unmarried. Finally, the EPIC cohort might be affected by a “healthy worker effect”, as the cohort members were recruited from general population and only 37% participated  as compared to 86% participation rate in the Danish Nurse Cohort.  While the percentage of never smokers was 36% in the Danish Nurse Cohort, it was 43% in the Danish EPIC cohort. 
We found the highest risk of breast cancer related to smoking heavily before the 1st childbirth, in agreement with existing evidence. [6,7,8, 10,11,12] Breast development with increased epithelial cell proliferation begins before the menarche,  while the terminal differentiation of the breast epithelium takes place in the last trimester of pregnancy.  It is therefore plausible that the time before the 1st pregnancy may be critical for susceptibility to tobacco smoke carcinogens. In contrast to the EPIC study,  no protective effect of smoking in postmenopausal age was found in either American  or Danish nurses.
As alcohol is an established risk factor for breast cancer, and as alcohol and smoking often come together, the possible confounding by alcohol of the effect of smoking on the risk of breast cancer has been debated in literature. Alcohol has also been previously shown to be an independent risk factor for breast cancer in the Danish Nurse Cohort.  However, alcohol did not seem to be a confounder in our study. Our risk estimates were adjusted for intensity of alcohol consumption. The breast cancer risk was somewhat enhanced in heavy drinking current smokers, but, in line with the results of the EPIC study,  the trend of increase in risk of smoking by increasing level of alcohol consumption was not statistically significant neither for ever nor for current smokers (Table 4). The available data thus indicate that the effect of smoking on breast cancer risk is independent of the effect of alcohol.
We contribute with novel data on smoking and subtypes of breast cancer, as only a few studies have previously included this information. [7, 10, 11, 13] We detected a very strong association between current (vs. never) smoking and ER+/PR- breast cancer (1.92; 1.19–3.10), followed by a weaker but robust association with ER+/PR+ breast cancer (1.36; 1.06–1.76), and none for ER−/PR- or ER−/PR+ breast cancers. This is in agreement with EPIC study, which reported the strongest risk related to current smoking of 34% for ER+/PR-, 23% for ER+/PR+, and 13% for ER−/PR-,  and American Retired women study which found 37% increased risk of ER+/PR- breast cancer in current smokers, and none with ER+/PR+ or ER−/PR- subtypes.  Luo et al. has reported a 28% increased risk of ER+/PR+ breast cancer in current compared to never smoker, but in contrast to our study and current literature, none with ER+/PR- or ER−/PR-,  whereas Gaudet et al. reported association with smoking limited to ER+ breast cancer subtype, and none with ER-, but lacked data on PR status. 
Strengths of this study include data from a large prospective nationwide cohort with comprehensive follow-up of both vital status and incident breast cancer cases from linkage with nationwide registers. Exposure information from the cohort was expected to be valid as already known associations between breast cancer and, for instance, alcohol use  and HT [26,27,28] have already been documented in this cohort. Another strength was the high smoking prevalence, where 34% of women in our cohort were current smokers. This means that potential confounding not controlled for will affect our results less than is the case in the studies where smokers constitute a smaller, and thus a more marginalized group of women.
The main limitation was the exposure misclassification as the smoking exposure was based on questionnaires at the time of recruitment, without follow-up, and the lack of information on passive tobacco smoke. However, prevalence of active and passive smoking in Denmark in this period was high, and based on data from a related Danish Diet, Cancer and Health cohort recruited in the same period, we estimated earlier that only 5% of women in this period were not exposed to passive smoke at home or work.  In any case, passive smoking is difficult to assess accurately, due to its ubiquitous exposure, and the American nurses study failed to find an association between passive smoking and breast cancer,  while the EPIC study found that excluding passive smokers from the reference group led to higher risk estimates for active smoking. 
Danish nurses have been found to live a generally healthier lifestyle than a representative sample of Danish women, as they smoked less and had higher physical activity levels, although they consumed more alcohol.  Furthermore, there was no major differences between Danish nurses and Danish women in general with respect to use of health care and disease occurrence.  It is therefore reasonable to generalize the findings based on the Danish Nurses Cohort to Danish women in general.