In the most comprehensive review to date of how breast cancer develops, scientists have created a detailed map that describes the many ways in which environmental chemicals can trigger the disease.
Using ionizing radiation as a model, the researchers identified key mechanisms within cells that when disrupted cause breast cancer. Because the findings can be generalized to other environmental carcinogens, they could help regulators identify chemicals that increase breast cancer risk.
“We know exposure to toxic chemicals can play an important role in the development of breast cancer,” says Ruthann Rudel, an environmental toxicologist at Silent Spring Institute and one of the study’s co-authors.
“Yet, when regulators try to evaluate whether a chemical is harmful or not, the tests they use do not capture the effects on the breast. This gap in testing means potential breast carcinogens are being given the green light for use in our consumer products.”
Breast cancer is the most common invasive cancer in women, with incidence rates highest in North America and Europe, and rates increasing globally. Because only 5 to 10 percent of breast cancers are due to high risk inherited mutations, such as BRCA1 and BRCA2, scientists say a better understanding of how environmental factors contribute to the disease is needed to prevent future breast cancers and lower incidence rates.
Toward that end, researchers at Silent Spring looked at ionizing radiation—an established risk factor for breast cancer. People can be exposed to ionizing radiation from many sources, including X-rays, CT scans and radiation treatment.
The effects of radiation on breast cancer have been extensively studied, based in large part on studies of survivors of the atomic bombings in Hiroshima and Nagasaki and women who were exposed to medical radiation as adolescents.
Reporting in the journal Archives of Toxicology, Rudel and co-author Jessica Helm reviewed 467 studies to identify the sequence of biological changes that occur in breast cells and tissue from the time of radiation exposure to the formation of a tumor.
They then created a map of these sequential changes, revealing multiple interconnected pathways by which ionizing radiation leads to breast cancer.
The researchers created the map using a framework called an Adverse Outcome Pathway (AOP). AOPs were designed by the Organisation for Economic Co-operation and Development (OECD) as a way to represent how complex diseases develop, and to help regulators, chemical manufacturers, and drug companies predict how chemicals might affect diseases early in the research process.
“It turns out, not surprising, breast cancer is a lot more complex than how it’s conveyed in traditional cancer models,” says Rudel. In traditional models, ionizing radiation triggers breast cancer solely through DNA damage.
The new model by Silent Spring integrates recent findings in cancer biology that show radiation, in addition to DNA damage, also increases the production of molecules called reactive oxygen and nitrogen species.
These molecules wreak havoc inside cells, causing inflammation, altering DNA, and disrupting other important biological activities.
“This study is important and highlights the need for a holistic consideration of mechanistic evidence when identifying potential carcinogens,” says Kathryn Guyton, a senior toxicologist at the International Agency for Research on Cancer.
“In reality there are multiple key characteristics of carcinogens. Increasingly, we are appreciating that human carcinogens may exhibit different combinations of these key characteristics.”
The Silent Spring team also found that the biological changes that lead to breast cancer are highly influenced by reproductive hormones, such as estrogen and progesterone.
Reproductive hormones stimulate the proliferation of cells within the breast, so chemicals that similarly encourage cell proliferation could make the breast more susceptible to tumors.
“Critical periods of development, such as during puberty or pregnancy when the breast undergoes important changes, are times when the breast is especially vulnerable,” says Rudel.
To address gaps in chemical safety testing, the Silent Spring researchers identified a series of tests regulators could use to find chemicals that disrupt the pathways outlined in their new model.
Chemicals that disrupt these pathways would be considered potential breast carcinogens, thereby discouraging their use in products.
“This study is an invaluable contribution to the field and a real wake-up call for regulators,” says Linda Birnbaum, former director of the National Institute for Environmental Health Sciences.
“By holding on to an oversimplified model of how chemicals cause cancer, regulators have been missing critical information, potentially allowing toxic chemicals to enter our products, our air, and our water.”
The AOP project is part of Silent Spring Institute’s Safer Chemicals Program which is developing new cost-effective ways of screening chemicals for their effects on the breast. Knowledge generated by this effort will help government agencies regulate chemicals more effectively and assist companies in developing safer products.
Windows of susceptibility (WOS)
Breast cancer etiology appears to be driven in part by perturbations to breast tissue as well as alterations of the mammary gland micro-environment during critical windows. Here we briefly summarize breast tissue changes occurring during each WOS, review evidence that addresses environmental carcinogenesis during each WOS, and outline the motivation for ongoing research on the chemicals and metals targeted in BCERP.
The prenatal period is a particularly vulnerable WOS because breast tissue begins to develop in the embryonic stage when epidermal cells in concert with embryonic mesenchyme become breast buds [15,16,17,18].
Faster fetal growth and greater birth-weight increase breast cancer risk later in life [19,20,21]. Proposed mechanisms by which chemicals can alter normal mammary development trajectories [15, 18, 19, 22, 23] include changes in maternal hormone levels regulating development and sex differentiation, high levels of growth factors, potential DNA damage and mutations in germ cells, and other genetic or epigenetic processes .
Pregnancy and birth cohorts reveal possible associations between environmental chemicals during the prenatal period and breast cancer. The Child Health and Development Studies (CHDS) found high levels of maternal exposure to dichlorodiphenyltrichloroethane (DDT) during pregnancy increased the daughters’ later breast cancer risk to age 52 nearly fourfold compared to daughters of women with low levels of exposure (Table 1) .
Although production of many of the organochlorine chemicals—including dioxins, polychlorinated biphenyls (PCBs), and pesticides such as DDT—stopped in the 1970s, there is continued exposure to these complex mixtures with diverse biological activity.
Animal fats and fish from contaminated waters are on-going sources of human exposure as a result of bioaccumulation ; PCB exposure also persists through inhalation both outdoors and of indoor air and dust from caulk, building materials, and floor finishes .
Organochlorines are hormonally active and may contribute to breast cancer by altering mammary gland development or hormone responsiveness early in life, or by promoting tumor growth . Epidemiologic studies of DDT exposure measured outside of a WOS and breast cancer risk were less likely to report consistent findings [14, 19].
Table 1 Epidemiologic studies investigating environmental exposures during three windows of susceptibility in relation to an intermediate marker of breast cancer risk or breast cancer
|First author (Year)||Exposure||Outcome||Population||Sample size||Risk estimate||95% CI||Notes|
|Exposure during prenatal window|
|Bonner (2005) ||Regional total suspended particulates||Breast cancer||Women 35–79, New York||1166 cases and 2105 controls||OR 2.42||0.97–6.09||> 140 vs < 84 μg/m3 TSP, postmenopausal women|
|OR 1.78||0.62–5.10||> 140 vs < 84 μg/m3 TSP, premenopausal women|
|Bocskay (2005) ||Personal airborne PAH; PAH DNA adducts||Chromosomal aberrations from cord blood||Newborns in Northern Manhattan; Bronx||60 (32 female, 28 male)||Data not shown for PAH adducts||“No strong association”|
β = 0.14
|p = 0.006||Linear regression line slope|
|Cohn (2015) ||Maternal o,p’-DDT||Daughter breast cancer||Mothers and adult daughters in Alameda County, CA||118 cases and 354 controls||OR 3.7||1.5–9.0||Fourth vs first quartile (> 0.78 vs < 0.27 ng/mL)|
|Exposure during puberty window|
|Tsai (2015) ||Serum PFOA||log-transformed SHBG||Taiwanese girls aged 12–17||65||2.96 (SE 0.34) vs 3.50 (SE 0.24)||p < 0.05||Mean PFOA levels 90th vs 50th percentile (> 9.80 vs < 3.63 ng/mL)|
|Data not shown||p > 0.05||FSH and testosterone|
|Wolff (2015) ||Urinary phenols||Age at breast development||US girls aged 6–8 followed for 7 years||1239 girls||Enterolactone: HR 0.79|
Benzophenone-3: HR 0.80
2,5-dichlophenol: HR 1.37
|5th vs 1st quintiles of biomarkers|
|Wolff (2014) ||Low and high molecular weight phthalate (MWP) metabolites from urine||Age of breast and pubic hair development||US girls aged 6–8 followed for 7 years||1239 girls||Pubic hair development age: HR 0.91|
Breast development age: HR 0.99
|5th vs 1st quintiles of high MWP metabolites. Results null for low MWP metabolites.|
|Wolff (2010) ||Low and high molecular weight phthalate (MWP) metabolites from urine||Stage of breast and pubic hair development||US girls aged 6–8 followed for 1 year||1151 girls||Pubic hair development:|
|5th vs 1st quintiles of high MWP metabolites. Results attenuated for low MWP metabolites (p = 0.08).|
|Windham (2015) ||PBDE, PCB, OCP||Tanner stage 2+ vs 1 (breast development)||US girls aged 6–8 followed for 7 years||645 girls||PBDE: TR 1.05|
PCB: TR 1.05
OCP: TR 1.10
|4th vs 1st quartile. Results similar for pubic hair development.|
|Cohn (2007, 2019) [67, 68]||p,p’-DDT metabolites in serum taken after giving birth (initial DDT exposure likely before age 14 years)||Breast cancer before age 50||Women in Child Health and Development Studies cohort||129 cases and 129 matched controls||OR 5.4||1.7–17.1||Highest vs lowest tertile (> 13.90 vs < 8.09 μg/L)|
|Breast cancer diagnosis during ages 50–54||153 cases and 432 matched controls||OR 1.88||1.37–2.59||One-unit change in log2 (p,p’-DDT), approximately equal to a 2-fold increase|
|Exposure during pregnancy|
|Nie (2007) ||Regional total suspended particulates at time of first birth||Post-menopausal breast cancer||Women 35–79 in Erie and Niagara Counties||220 cases and 301 controls||OR 2.57||1.16–5.69||Highest vs lowest quartile|
|Bonefeld-Jorgensen (2014) ||16 serum PFAS during pregnancy including 10 PFCA, 5 PFSA, and PFOSA||Breast cancer||Danish National Birth Cohort||250 cases and 233 controls||PFOSA: RR 1.04|
PFHxS: RR 0.66
|Continuous per ng/ml. All other PFAS were null.|
|Cohn (2012) ||Serum PCB during early postpartum||Breast cancer before age 50||Women in Child Health and Development Studies cohort||112 cases with matched controls||PCB 167:|
|Highest vs lowest quartile (> 0.30 vs < 0.08 mmol/l)|
(> 0.66 vs < 0.38 mmol/l)
(> 0.42 vs < 0.34 mmol/l)
- Abbreviations: AA African American, BMI body mass index, FSH follicle-stimulating hormone, HR hazard ratio, IRR incidence rate ratio, NHANES National Health and Nutrition Examination Survey, OR odds ratio, PAH polycyclic aromatic hydrocarbons, PFAS perfluoroalkylated substances, PFHxS perfluorohexanesulfonate, PFOA perfluorooctanoic acid, PFOSA perflurooctane-sulfonamide, PR prevalence ratio, RR relative risk, SHBG sex hormone-binding globulin, TR time ratio of median ages across quantile groups
Another class of chemical exposures of concern during the prenatal WOS is polycyclic aromatic hydrocarbons (PAH). PAH are produced as a result of combustion of hydrocarbons.
Some of the common sources of PAH exposure include consuming grilled meats and certain other food items , inhaling cigarette smoke and motor vehicle exhaust , and exposure to industrial processes [29,30,31].
PAH are widespread and enter the body largely through ingestion and inhalation of suspended particulate matter [32, 33]. The International Agency for Research on Cancer classifies PAH as probable carcinogens; the US Environmental Protection Agency lists PAH as possible carcinogens [34, 35].
Like DDT and other organochlorines, PAH are lipophilic and stored in fat tissue including breast tissue . Most PAH compounds are weakly estrogenic and may induce cell proliferation via activation of the estrogen receptor (ER) .
Exposure to PAH was linked to mammary cancer in rodents . PAH exposure has been measured directly in both blood  and breast tissue , and higher levels of PAH-DNA adducts have been found in breast cancer cases compared with women without breast cancer .
Similarly, breast cancer cases reported higher levels of PAH exposures than controls based on questionnaire assessments of indirect exposure [42,43,44,45,46]. For all these epidemiologic studies, specific WOS were not investigated.
Because experimental and epidemiologic associations implicate prenatal PAH exposure in multiple adverse health effects including obesity [47,48,49], one focus of BCERP is the impact of PAH exposure during the prenatal WOS.
BCERP research specifically addresses how exposure to PAH during the prenatal and pregnancy WOS may increase the development of mammary tumors in mice. Concurrent human studies within BCERP evaluate how prenatal PAH exposure alters breast tissue development and tissue composition in adolescent girls.
Pubertal window of susceptibility
The female breast undergoes rapid changes and growth during puberty. The highest density of proliferating terminal end buds that mediate ductal elongation and establishment of the ductal tree and primitive lobular structures form during puberty [50, 51].
This time period is considered highly estrogen sensitive based on evidence in mice where pubertal growth is almost completely stunted in mice lacking ERα [52, 53]. The profound hormonal changes, including a dramatic increase in endogenous estrogen biosynthesis by stimulating hormones from the hypothalamus and pituitary gland, culminate in the onset of menarche.
Endocrine-disrupting chemicals (EDC) in the environment may affect the interaction of endogenous estrogens and progestogens with their receptors and together have carcinogenic impact. Exposure to EDC may reprogram normal stem cells which are subsequently transformed by additional estrogen exposures .
The number of mammary stem cells expands during this period of proliferation, and these cells distribute throughout the ductal tree . Three previous BCERP puberty cohorts examined exposure to several environmental chemicals in relation to pubertal timing as endpoints and reported that higher levels of some (but not all) chemicals, including various phenols (including bisphenol A [BPA]), parabens, phthalates, and persistent organohalogenated compounds, were associated with delayed median puberty endpoints by 5–11 months when comparing extreme categories of exposure (Table 1) [56,57,58,59,60].
Epidemiologic and experimental evidence from investigators outside of BCERP suggest environmental exposures during the pubertal WOS are associated with an increase in breast cancer risk. Human studies have examined high doses of radiation from medical treatment or atomic bomb exposure [61, 62] and nutritional exposures during puberty and adolescence [63,64,65,66].
DDT exposure during infancy and puberty was associated with increased breast cancer risk [67, 68]. In experimental studies of rats, exposure to a carcinogen (dimethylbenz [a] anthracene, DMBA) resulted in the highest number of tumors when administered to rodents during “puberty” possibly through induction of proinflammatory responses [50, 51, 69,70,71,72,73,74].
Excessive signaling through the ER appears to be another primary mechanism for mammary carcinogenesis as modest overexpression of ERα in response to endogenous estrogen during puberty in transgenic mice resulted in mammary hyperplasia and tumors [75, 76].
BCERP members are studying the effect of pubertal levels of perfluorooctanoic acid (PFOA) and per- and polyfluoralkyl substances (PFAS) on breast development and breast density. PFAS are used in many commercial products because of their non-stick, stain-resistant, and waterproof characteristics.
Sources of human exposure include production facilities, firefighting training, consumer products, diet, and drinking water. Dietary sources include seafood  and food packaging . PFAS enhance the estrogenic effects of 17β-estradiol in T47D human breast cancer cells  and promote the proliferation, migration and invasion potential of human breast epithelial cells . A
nimal studies provide evidence that PFOA affects the developing mammary gland , although limited human epidemiologic data have been less conclusive when PFOA and PFAS exposure was examined in relation to intermediate breast cancer markers (hormone levels)  or measured during adulthood .
Because environmental chemicals may influence the timing and duration of the pubertal trajectory, studies including breast tissue biomarkers that can be reliably measured to provide greater information than a single event in time, such as age at menarche, are critical to move the field forward.
Pregnancy window of susceptibility
Pregnancy is another period of rapid breast tissue and micro-environmental changes during which susceptibility to environmental exposures may increase the risk of breast cancer . During pregnancy, breast tissue changes rapidly in size and function to prepare for lactation.
Estrogen, progesterone, and prolactin are the major drivers of branching and development of the lobuloalveolar structures’ characteristic of the mature breast . Pregnancy also decreases the number of mammary stem cells [85, 86]. However, the protective pathways activated during pregnancy can be eroded by prolonged exposure to exogenous 17β-estradiol which restores sensitivity to carcinogen-induced mammary tumors [87,88,89].
These observations may explain why pregnancy is accompanied by a short-term increase in breast cancer risk [12, 90]; “pregnancy-associated breast cancer” has poorer overall survival [91, 92].
However, in the long term after a pregnancy, breast cells are less sensitive to carcinogenesis with the lifetime risk of breast cancer reduced by up to 50% [93,94,95,96]. Thus, the mechanisms mediating the competition between tumor-promoting and tumor-suppressive effects of estrogens in the breast provide fundamental insights into mechanisms underlying risk and resistance in the presence of environmental chemicals.
In mice, there is a greater than 100-fold increase in the number of mammary epithelial cells during pregnancy demonstrating the rapid changes that occur in mammary tissue. Despite the rapid proliferation, a full-term pregnancy renders the mammary epithelium resistant to tumorigenesis subsequent to the pregnancy.
This is observed in studies of exposure to carcinogens [70, 97,98,99] as well as inherited genetic risk alleles [100,101,102,103]. Administering exogenous estrogen, either alone or in combination with progesterone to rodents at an early age, sufficiently mimics the effect of pregnancy in reducing tumors in rodents [104,105,106].
Lobuloalveolar structures may be less susceptible to carcinogens [107, 108], in part, through more robust p53-dependent responses to DNA damage .
Epidemiologic evidence directly linking environmental exposures during pregnancy and breast cancer risk arises from the previously mentioned prospective CHDS which measured PCB and DDT soon after pregnancy and confirmed breast cancer diagnoses with medical records.
Relative risk estimates for breast cancer comparing upper to lower quartiles of 16 individual PCB congeners ranged from 0.2 to 6.3; a composite score of exposure was associated with an odds ratio of 2.8 (95% CI 1.1–7.1) (Table 1) .
Other epidemiologic studies suggest no association between breast cancer and organochlorine pesticide residues in blood collected near the time of diagnosis [111, 112], but these measurements may not be representative of exposure to the parent chemical during the relevant WOS .
The BCERP consortium is studying the effects of exposure during pregnancy on maternal breast cancer risk by examining breast tissue changes in the mothers of daughters participating in studies at the Columbia’s Children Center for Environmental Health [32, 114].
The design of this mother-daughter cohort, similar to CHDS, facilitates efficient examination of exposure to PAH during two WOS (pregnancy and prenatal) in the two generations .
As a complement to this epidemiologic study, other BCERP members aim to elucidate the mechanisms for the dual effect of pregnancy on breast cancer risk by examining chemicals that are found in higher levels among pregnant women [116, 117] and their potential to impair the protective pathways associated with breast development during pregnancy. These pathways include the activity of p53  and limiting the stem cell populations .
Menopausal transition window of susceptibility
Although menopause is often defined as the cessation of menstrual periods for at least 1 year, the menopausal transition begins a number of years prior to menopause. During the menopausal transition, micro-environment changes occur in the breast tissue along with declining systemic levels of endogenous estrogen and progesterone .
As the majority of breast cancers are responsive to these two sex steroid hormones, their decline explains the leveling-off of the age-specific rate curve of breast cancer after menopause .
Later age at menopause is associated with a higher risk of developing breast cancer due to a longer period of exposure to higher levels of sex steroid hormones . Despite the leveling in the age-specific rate curve of breast cancer, the vast majority of breast cancers are diagnosed after menopause, in part through enhanced hormone receptor sensitivity during the menopausal transition.
Mammary tissue may be more responsive to lower levels of estrogen and progesterone, as well as to hormone mimics, by adapting to the abrupt reduced production of ovarian hormones [122, 123].
Analyses of data from the Women’s Health Initiative (WHI) showed that the increased incidence of breast cancer with use of exogenous estrogen and progesterone [124,125,126,127] was mediated through the change in mammographic breast density that occurred in the first year of use .
A biologically based breast tumor growth rate model  suggests that hormone therapy promotes growth of pre-existing occult lesions and minimally initiated de novo tumors. EDCs with estrogen-like and/or progesterone-like activities or those modifying aromatase expression/activity including polybrominated diphenyl ethers (PBDE), BPA, or selected metals may act in a similar manner and promote the growth of occult disease to clinically detectable tumors during the menopausal transition.
PBDE are a class of over 200 organohalogenated compounds widely used as flame retardants and may modulate steroidogenesis including expression of aromatase [130,131,132,133,134,135,136].
BPA is an industrial chemical found in polycarbonate plastics, epoxy resins, dental sealants, and thermal paper [137, 138]. Both PBDE  and BPA  have been shown to act as ligands of ERα. While experimental studies suggest that PBDE and BPA cause breast cancer and biomonitoring studies confirm that women are exposed, epidemiologic studies have not to-date measured exposure during relevant WOS, used methods that reflect long-term exposure, or included measures of mammographic density or other intermediate markers of breast cancer risk [138, 140, 141].
Metalloestrogens are metals that activate the ER, leading to estrogen-like changes. Metalloestrogens are prevalent environmental contaminants with multiple routes of human exposure.
They often accumulate in tissues and organs (reviewed in [142, 143]). Most breast cancer studies have focused on cadmium which induces the proliferation of estrogen-dependent breast cancer cells [144,145,146,147], increases the transcription and expression of estrogen-regulated genes such as the PR [144, 148], activates ERα in transfection assays [144,145,146, 149, 150], and increases signaling through the ERK1/2 and Akt pathways [148, 151, 152].
The reported associations between metalloestrogen exposures and breast cancer risk to date have been inconsistent in part due to the variety of techniques used to assess exposure.
Studies of dietary cadmium measured from self-reported dietary assessments and breast cancer risk have on the most part found minimal if any associations due in part to the difficulty in determining exposure [153,154,155,156,157,158,159].
The studies of neighborhood airborne levels did not distinguish differences between breast cancer cases and controls [160, 161]. The studies measuring individual cadmium levels from blood, urine, or toenails are not necessarily measuring the same timing of exposure. Most [153,154,155, 159, 162, 163], but not all [158, 164], epidemiologic studies of postmenopausal women or all ages combined show risk estimates in the 0.73 to 1.01 range (Table 2).
Two studies show greater risk associated with cadmium exposure for premenopausal women than for postmenopausal women [156, 165], whereas two other studies show the reverse [157, 166], with additional studies describing generally null associations for both groups [160, 161, 167, 168].
Stratification by estrogen receptor status does not reveal a consistent pattern. Studies of cadmium and mammographic breast density as an intermediate marker of breast cancer risk also have mixed findings possibly due to differences in assessment of cadmium or breast density in terms of methods and in timing relative to WOS [168,169,170,171].
Exposure to cadmium or other metalloestrogens during any of the WOS may impact a woman’s risk of breast cancer by activation of the hormone receptors; however, no studies as of yet have carefully examined whether metalloestrogens may have the greatest impact during the menopausal transition when endogenous hormone levels are declining.
Table 2 Epidemiologic studies investigating cadmium exposure in relation to breast cancer risk according to the menopause window of susceptibility (WOS)
|First author (year)||Exposure||Population||Sample size||Risk estimate||95% CI||Notes|
|Cadmium exposure stratified by menopausal status|
|McElroy (2006) ||Urinary cadmium||Women aged 20–69 years||246 cases and 254 controls||All ages OR 2.29|
20–56 years OR 2.34
57–69 years OR 1.36
|Highest (≥ 0.58) vs lowest (< 0.263 μg/g) quartile|
|Gallagher (2010) ||Urinary cadmium||Long Island (LI), NY and NHANES women aged ≥ 30 years||LI 100 cases and 98 controls|
NHANES 99 cases and 3120 non-cases
|All ages OR 2.81|
n.s. difference by age
All ages OR 2.32
30–54 years OR n.s.
≥ 55 years OR 7.25
|Highest (≥ 0.60) vs lowest (< 0.22 μg/g creatinine) quartile|
|Itoh (2014) ||Dietary cadmium||Japanese women aged 20–74 years||212 cases and 253 controls||All cases OR 1.04|
Premeno. OR 1.01
Postmeno. OR 1.06 Post. ER+ OR 1.08
Post. ER− OR 0.99
|Continuous cadmium intake (μg/day)|
|Amadou (2019) ||Long-term airborne exposure to cadmium||E3N French cohort aged 40–65 years||4059 cases and 4059 controls||Overall OR 0.98|
Premeno OR 0.72
Postmeno. OR 1.06
ER+ OR 1.00
ER− OR 0.63
|Highest (> 5.47) vs lowest (≤ 0.033 mg/m2) quintile|
|Grioni (2019) ||Dietary cadmium||Italian cohort aged 34–70 years||8924 total in cohort with 481 cases||Overall HR 1.54|
Premeno HR 1.73
Postmeno HR 1.29
ER+ HR 1.64
ER− HR 1.30
|Highest (≥ 8.82) vs lowest (< 6.73 μg/day) quintile|
|O’Brien (2019) ||Cadmium from toenail clippings||Sister and two-sister studies aged < 50 years||1217 sister-pairs of cases and controls||OR 1.15||0.82–1.60||Highest (> 0.011) vs lowest (< 0.003 μg/g) quartile|
| White (2019)|
|Residential census tract airborne exposure to cadmium at baseline||Sister study aged 35–74 years||50,884 total in cohort with 2587 cases||Overall HR 1.1|
|Highest vs lowest quintile|
|Postmenopausal women only|
|Julin (2012) ||Dietary cadmium||Swedish postmenopausal women||55,987 total in cohort with 2112 cases||All cases RR 1.21|
ER+ cases RR 1.19
ER− cases RR 1.33
|Highest (> 16) vs lowest (< 13 μg/day) tertile|
|Adams (2012) ||Dietary cadmium||Postmenopausal women in VITamines And Lifestyle cohort||30,543 total in cohort with 899 cases||HR 1.00|
n.s. difference by ER status (p = 0.11)
|0.72–1.41||Highest (> 13.3) vs lowest (< 7.48 μg/day) quartile|
|Eriksen (2014) ||Dietary cadmium||Danish postmenopausal women||23,815 total in cohort with 1390 breast cancer cases||All cases IRR 0.99|
ER+ IRR 1.00
ER− IRR 0.88
|Per 10 μg/day increase in intake|
|Adams (2014) ||Dietary cadmium||Postmenopausal women aged 50–79 years||155,069 total in cohort with 6658 cases||HR 0.90|
n.s. difference by ER status
|0.81–1.00||Highest (> 14.21) vs lowest (< 7.10 μg/day) quintile|
|Adams (2016) ||Urinary cadmium||Postmenopausal women ages ≥ 50 years in Women’s Health Initiative||12,701 total in cohort with 508 cases and 1050 controls||All HR 0.80|
ER+ HR 0.98
ER−/PR- HR 0.88
|Highest (> 0.748) vs lowest (< 0.325 μg/g creatinine) quartile|
|Sawada (2012) ||Dietary cadmium||Japanese women aged 45–74 years||48,351 females total in cohort with 402 breast cancer cases||HR 0.87||0.61–1.23||Highest (median 32.3) vs lowest (median 19.2 μg/day) tertile|
|Nagata (2013) ||Urinary cadmium||Japanese women ages ≥ 25 years||153 cases from one hospital and 431 controls invited for breast cancer screening||OR 6.05||2.90–12.62||Highest (> 2.620) vs lowest (< 1.674 μg/g creatinine) tertile|
|Gaudet (2018) ||Blood cadmium||Cancer Prevention Study II women 47–85 years of age||816 cases and 816 controls||All RR 1.01|
ER+ RR 0.89
ER− RR 0.96
|Continuous per μg/L|
|Italian women aged 35–70 years||292 cases and 294 controls||RR 0.80||0.61–1.03||Continuous per μg/L|
|Swedish women aged 30–61 years||325 cases and 325 controls||RR 0.73||0.54–0.97||Continuous per μg/L|
|Combined 3 nested case-cohort studies||1433 cases and 1435 controls||RR 0.84||0.69–1.01||Continuous per μg/L|
- Abbreviations: BCSC Breast Cancer Surveillance Consortium, CI confidence interval, EPA Environmental Protection Agency, ER estrogen receptor, HR hazard ratio, IRR incidence rate ratio, NHANES National Health and Nutrition Examination Survey, n.s. not statistically significant, OR odds ratio, RR relative risk
BCERP members are examining whether exposure to PBDEs, BPA, or selected metals during the menopausal transition is associated with breast cancer risk in humans, and evaluating potential mechanisms to explain these associations in rodent models.
Strategies to address long latency
The long time between exposures during the early WOS (prenatal, puberty, pregnancy) and breast cancer occurrence has multiple implications for breast cancer research. First, because many environmental exposures are stored long-term in adipose tissue, even compounds now banned, such as DDT and PBDE, may continue to be relevant for breast cancer risk.
Bioaccumulation of lipophilic chemicals and their long-term storage also means studies incorporating biomarkers in breast tissue need to consider both the effects on adipose tissue as well as epithelial and stromal tissues.
Second, because it may be decades after the relevant windows of exposure before breast cancer is diagnosed, the examination and validation of intermediate biomarkers of response, apparent closer to the timing of exposure and before diagnosis, are imperative, particularly in prospective human studies.
BCERP first started as a cohort study of the environmental exposures that may accelerate puberty. The main outcome of the cohort study was based on Tanner Stages . As BCERP expanded to include other WOS, additional measures of breast tissue composition and breast density were added.
BCERP investigators are now using a variety of intermediate markers—as both outcomes in relation to chemical exposures and as predictors of breast and mammary cancers—conducted in parallel human and rodent studies including epigenetic biomarkers, altered tumor suppression and induction, and altered estrogen signaling and biosynthesis (Fig. 1) .
One intermediate outcome is mammographic breast density (MBD), defined as the fraction of connective and glandular tissue to adipose tissue on a mammogram [174,175,176,177,178,179,180,181]. MBD is one of the strongest predictors of breast cancer risk with a four- to sixfold elevation in risk comparing ≥ 75% MBD to < 5% , but the mechanisms explaining how environmental chemicals affect the overall level and rate of change of MBD are uncertain. While MBD declines with age in many women, particularly around the time of menopause [183,184,185], this pattern does not occur uniformly for all women [8, 186, 187].
Little is known of the drivers of breast tissue changes across adolescence, early adulthood, and the menopausal transition and thus the contributors to breast density. Most of what is known about normal breast tissue characteristics is from mammography data in women over 40 years of age.
In women under 40 years, two alternative imaging methods have been used to assess breast composition including three studies of magnetic resonance imaging (MRI) in women aged 15–30 years [188,189,190] and two of dual X-ray absorptiometry (DXA) in girls aged 10–16 years [191, 192].
In addition, optical spectroscopy (OS) provides a compositional view of the breast capturing variation in the amount of water, lipid, hemoglobin, and collagen, as well as overall cellular and connective tissue density [174,175,176]. Collagen density may promote epithelial cell proliferation and increase tumor mobility and invasion, while hemoglobin is associated with angiogenesis [193,194,195].
OS has been used to measure differences in adolescent breast tissue across developmental stages as assessed by Tanner stage . Thus, MRI, DXA, and OS provide novel intermediate outcomes to measure breast tissue changes across the developmental trajectory of adolescence and early adulthood and may be important tools for examining environmental effects during these life stages.
Mammography techniques now include digital breast tomosynthesis measures as well as the use of ultrasound in measuring breast density without radiation exposure . While density of the adult breast is highly correlated with breast cancer risk, longitudinal measures of pubertal density are currently lacking but are being collected in BCERP.
More information: Jessica S. Helm et al, Adverse outcome pathways for ionizing radiation and breast cancer involve direct and indirect DNA damage, oxidative stress, inflammation, genomic instability, and interaction with hormonal regulation of the breast, Archives of Toxicology (2020). DOI: 10.1007/s00204-020-02752-z