Environmental and Genetic Risk Factors For Breast Cancer: The Sister Study

National Institute Of Environmental Health Sciences

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Abstract

We are following 50,884 US women who were aged 35-74 and breast cancer free but had a sister previously diagnosed with breast cancer when they enrolled in 2003-2009. Data on potential risk factors and health were collected in computer-assisted telephone interviews. Anthropometric and blood pressure measurements, and blood, urine, toenails, and dust samples were collected in home visits. To date, over 4,600 participants have reported incident breast cancer. The cohort is contacted annually for major health changes. Detailed follow-up questionnaires are completed every 3 years. Medical records are retrieved for cancers and other conditions. Tumor tissue is obtained for breast and ovarian cancers. Five follow-up surveys have been completed with response rates near 90%. The 6th detailed follow-up launched in fall 2023 and is ongoing. An Anniversary Biospecimen Collection (ABC) effort (blood, urine, stool) was piloted in the fall of 2024 and is now actively enrolling women. Sister Study research focuses on breast cancer and a range of other conditions through studies within the cohort and consortia efforts that pool data from multiple cohorts. Data collected from Sister Study participants were used for a variety of research projects during 2024-25. Many of these were overseen by Dr. Dale Sandler directly, but other NIEHS investigators (White, O’Brien, Goldberg, Jackson, Taylor, Weinberg) have also led studies. Sister Study data are also being used by investigators from NCI and the Sister Study contributes to large collaborative projects, such as the Premenopausal Breast Cancer Collaborative Group (PMBCCG) and other cancer consortia. Sister Study researchers have continued to conduct research in 5 main areas: (1) hormonal exposures and cancer in women; (2) the health impacts of chemical and environmental exposures; (3) genomics; (4) diet, obesity, and health; and (5) early life determinants of health. Hormonal exposures and cancer in women Women are exposed to hormones throughout their lives from both endogenous and exogenous sources. Factors that impact exposure levels are thought to influence carcinogenesis, particularly for cancers of the breast, ovary, and uterus. In one Sister Study analysis, researchers considered whether age at first period and age at breast development were associated with ovarian cancer, given that both are known to be inversely associated with breast cancer. No such associations were observed, though there may have been some differences by ovarian cancer histotype. Women’s breasts tend to decrease in density as women age and hormone levels decrease, but these changes happen at different rates across women. In an extramural-funded collaboration, investigators at Columbia found that having stable or increasing mammographic density was associated with increased breast cancer risk, compared to women who lost breast density over time. These findings may help guide clinical recommendations for incorporating mammographic density trajectories in risk assessments, including support for increased monitoring of women who do not experience breast density loss over time. In an analysis that pooled Sister Study data with data from 9 other prospective cohorts participating in the PMBCCG, unopposed estrogen therapy use was found to be inversely associated with breast cancer before age 55 and estrogen plus progestin hormone therapy use was positively associated with breast cancer before age 55. The positive association between estrogen plus progestin therapy and young-onset breast cancer was stronger for longer-term use and among women without hysterectomy or bilateral oophorectomy. These results are similar to prior studies of hormone use and later-onset breast cancer but provide novel evidence for informing clinical recommendations for hormone therapy use in young women. Another pooled analysis conducted within the PMBCCG developed a prediction model for premenopausal breast cancer. The relative contributions of each factor in the prediction model (age, age at menarche, number of births, height, body mass index, first-degree family history of breast cancer, and personal history of benign breast disease) were similar to models previously developed to predict all breast cancer, highlighting the need to identify factors that more specifically predict premenopausal disease risk. Health impacts of chemical and environmental exposures The Sister Study evaluated the health impacts of a wide range of potential chemical and environmental exposures, from air pollution to medications to personal care products. In one study of industrial air pollution, women exposed to higher levels of certain chemicals, like nickel compounds and trichloroethylene, had an increased risk of developing breast cancer later in life. Most of the chemicals studied showed no clear link to breast cancer, suggesting that while a few specific pollutants may contribute to risk, industrial air pollution as a whole does not appear to be a major driver of breast cancer incidence. However, because exposure levels among women in the Sister Study were relatively low, further research is needed to determine whether stronger associations exist in populations with a greater burden of exposure to industrial pollution and to better evaluate long-term health effects. Another study measured the association outdoor air pollution exposure, including nitrogen dioxide (NO2), particulate matter (PM2.5), and ozone (O3), and incidence of ovarian cancer. Women with higher NO2 levels, which are often an indication of high traffic pollution, had higher rates of ovarian cancer. The relationship between ovarian cancer and exposure to PM2.5 or O3 was less consistent. These findings suggest that air pollution, particularly NO2, may play a role in ovarian cancer development. Another Sister Study investigation reported a positive association between estimated levels of certain airborne phthalates, independently and as a mixture, and higher prevalence of hypertension. A history of depression was not associated with breast cancer risk, but antidepressant use, especially use of selective serotonin reuptake inhibitors (SSRIs), may be associated with a reduction in risk. This association was strongest in Sister Study participants with normal range or lower body mass index (<25 kg/m2) and contributes to our understanding of the long-term health effects of antidepressants. Chemical hair straighteners and relaxers often contain chemicals with endocrine-disrupting or carcinogenic properties, and Sister Study investigators have previously observed positive associations between self-reported use and cancers of the breast, ovaries, or uterus. More recently, Sister Study investigators found that frequent use of hair straighteners in early adolescence (ages 10-13 years) was linked to a higher risk of developing fibroids before age 36 in Black participants. The link was potentially stronger for women born between 1928-1945 and 1965-1974, possibly due to changes in hair straightener product formulations over time. Similar positive associations were observed among non-Hispanic White women, despite lower usage rates. This study highlights concerns over endocrine-disrupting and carcinogenic chemicals found in hair products and their potential role in hormone-related diseases. Genomics The Sister Study has contributed to many large pooled genetic studies looking for novel single nucleotide polymorphisms associated with breast cancer. Many of these studies have separately examined women of African descent or tried to identify causal mechanisms through pathway-based or transcriptomics-based approaches. The Sister Study also participates in the Cancer Risk Estimates Related to Susceptibility Genes (CARRIERS) consortium, the goal of which is to better understand the role of known pathogenic variants in determining breast cancer risk, include considerations of other established genetic and non-genetic risk factors, breast cancer invasiveness, and specific mutation types (e.g., truncating mutations). Some Sister Study specific projects have focused more specifically on the role of epigenetic factors in health. This includes a study examining how epigenetic predictors of protein levels in blood were associated with breast cancer. Here, several markers were linked to disease risk, including 8 proteins known to play a role in immune response. The observed links between predicted protein levels and breast cancer risk contribute new evidence to the hypothesis that changes to the immune system may impact breast cancer development. Diet, Obesity and Health Dietary factors, body fat, and nutrition are all important aspects of health, with established links to risk of breast cancer and many other chronic diseases. An important part to studying this topic well is ensuring that the data being collected is accurate. In a recently conducted reliability study, Sister Study investigators showed that self-reported height and weight can reliably be used to estimate BMI categories across socioeconomic, racial, and ethnic groups. Although weight and height were both generally underreported, when women were placed into BMI categories based on their self-reported versus objectively-measured BMI, there was high agreement across measures for all groups. In a large pooled analysis conducted using PMBCCG data from the Sister Study and 13 other prospective cohorts in the PMBCCG, investigators found that measures of central body fat, including waist circumference, were inversely associated with premenopausal breast cancer risk. However, this association was no longer seen once BMI was added to the statistical model. Overall, the analysis did not support an association between central adiposity and premenopausal breast cancer risk beyond the previously established inverse association between BMI and premenopausal breast cancer. Carotenoids are dietary compounds found in fruits and vegetables. High levels of carotenoids in blood have been shown to be associated with decreased risk of several diseases. Sister Study investigators sought to better understand the role of genetic factors in determining the relationship between fruit and vegetable consumption and carotenoid concentrations in blood to gain insights in how to better prevent chronic diseases. Genetic variants near the beta-carotene oxygenase 1 (BCO1) gene were associated with lutein and zeaxanthin levels, but no other strong genetic predictors were identified for any of the other 4 carotenoids (alpha-carotene, beta- carotene, cryptoxanthin, or lycopene). Collaborators at the University of North Carolina at Chapel Hill received a grant to study dietary and metabolic factors related to the risk of diverticulitis. In the first manuscript to be published from this project, investigators reported that contrary to current medical beliefs, higher dietary intake of nuts, seeds, and corn was not linked to an increased risk for developing diverticulitis. Overall healthy dietary patterns (which sometimes include nuts and seeds) were associated with a lower occurrence of diverticulitis. Early life determinants of health Early life experiences may have lasting impacts on health throughout adulthood due to stress, hormonal impacts, or epigenetic alterations. Co-authors from NCI and NIEHS found that in utero and newborn factors, such as having a higher birth weight or a mother who experienced high blood pressure or diabetes when pregnant, were associated with an increased incidence of thyroid cancer later in life. Another Sister Study investigation found that compared to women with older mothers, women born of mothers younger than 25 had a higher risk of having gynecologic surgery (including bilateral oophorectomy or hysterectomy) before the age 40, providing evidence that daughters of young mothers have worse gynecologic health. Trauma in early life (before age 18) is thought to affect overall health through stress pathways. In the Sister Study, 47% of participants reported at least one type of early-life trauma and 31% reported high multiple early-life traumas. Women reporting physical trauma (defined as being hit/attacked by someone) had the highest risk of gestational diabetes and pregnancy-related hypertension. Multiple early-life traumas were also associated with increased risk of these conditions. Another Sister Study project identified 108 areas of the epigenome that differed between those who did and did not experience any early life trauma. Two of the identified areas contained genes related to heart health and weight gain, providing evidence that trauma in early life may contribute to variability in DNA methylation. Both studies demonstrate how early life trauma can have lasting impacts on health. Other Papers Other recent papers using Sister Study data showed that use of certain everyday personal care products was associated with increased risk of asthma, that lack of greenspace was associated with poor sleep, and that increased levels of sedentary time were associated with increased risk of breast cancer.