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Plasma perfluoroalkyl substances and breast cancer risk in Brazilian women: a case-control study.

Itoh et al,

2025

Environ Health

This case-control study of 942 Brazilian women (471 with breast cancer and 471 matched controls) found that higher blood levels of certain per- and polyfluoroalkyl substances (PFAS)—persistent environmental chemicals found in products like non-stick cookware and food packaging—were significantly associated with increased breast cancer risk. Specifically, elevated concentrations of n-perfluoroheptane sulfonate (n-PFHpS) doubled the breast cancer risk, and this association was particularly strong for hormone receptor-positive breast cancers and varied by ethnicity. The study emphasizes the importance of analyzing specific PFAS chemical variants (isomers) rather than treating all PFAS as identical, as different forms showed different associations with breast cancer risk across ethnic groups. These findings add to growing evidence that PFAS exposure may be a modifiable environmental risk factor for breast cancer, though the researchers note that previous studies have shown mixed results.

Combined and progestagen-only hormonal contraceptives and breast cancer risk: A UK nested case-control study and meta-analysis.

Fitzpatrick et al,

2023

PLOS Med

A large UK study of nearly 10,000 breast cancer cases found that current or recent use of progestagen-only contraceptives (including pills, injections, implants, and IUDs) was associated with a 21-32% increased breast cancer risk, similar to the risk from combined oral contraceptives containing both estrogen and progestagen. The absolute risk increase is small and age-dependent: for women using hormonal contraceptives for 5 years, the excess risk translates to 8 additional breast cancer cases per 100,000 users among women aged 16-20, but rises to 265 additional cases per 100,000 users among women aged 35-39. While these findings add important evidence about hormonal contraceptive risks, the small increased risk must be weighed against the significant benefits of contraception during childbearing years, and women should discuss their individual risk-benefit profile with their healthcare providers when choosing contraceptive methods.

Urinary concentration of endocrine-disrupting phthalates and breast cancer risk in Indian women: A case-control study with a focus on mutations in phthalate-responsive genes.

Mukherjee Das et al,

2022

Cancer Epiemiol

The first Indian case-control study examining phthalates (chemicals widely used in plastics, cosmetics, and food packaging) and breast cancer found that women with higher urinary levels of di-butyl phthalate (DBP) had 1.5 times increased breast cancer risk, while those with higher DEHP levels had nearly 3 times increased risk. Analysis of breast tumor tissue revealed mutations in several genes known to respond to phthalate exposure, affecting pathways involved in hormones, metabolism, and cancer development. These findings suggest that exposure to certain phthalates may increase breast cancer risk through genetic changes, though larger studies are needed to confirm these results and understand how early-life exposures might contribute to cancer development later in life.

Oral Contraceptive Use and Breast Cancer Risk for BRCA1 and BRCA2 Mutation Carriers: Systematic Review and Meta-Analysis of Case-Control Studies.

Barańska et al,

2022

Cancers

This meta-analysis of nine studies involving over 33,000 women with BRCA1 or BRCA2 gene mutations. One significant finding was that women who first started using oral contraceptives at age 20 or older had a 21% increased risk of breast cancer compared to those who never used them. These findings suggest that the timing of oral contraceptive use may be important for women with BRCA mutations, though more research is needed to fully understand the relationship between hormonal contraception and cancer risk in genetic mutation carriers.

Testosterone therapy and risk of breast cancer development: a systematic review.

Ray et al,

2020

Curr Opin Urol

A systematic review identifying 22 cases of breast cancer in individuals on testosterone replacement therapy (TRT) found that 18 cases occurred in female-to-male (FtM) transgender individuals and only 4 in cisgender men, with testosterone treatment duration ranging from 5 weeks to 25 years at the time of diagnosis. The review noted a relatively higher incidence of breast cancer in FtM individuals on hormone therapy compared to cisgender men on TRT, though the small sample size prevents definitive conclusions about whether testosterone directly increases breast cancer risk or whether it should be contraindicated in those with prior breast cancer history. These findings highlight an important knowledge gap regarding the long-term cancer risks of gender-affirming hormone therapy and the need for larger, prospective studies to better understand the relationship between testosterone treatment and breast cancer development.

Association of Menopausal Hormone Therapy With Breast Cancer Incidence and Mortality During Long-term Follow-up of the Women’s Health Initiative Randomized Clinical Trials.

Chlebowski et al,

2020

JAMA

This long-term follow-up study of over 27,000 postmenopausal women in the Women’s Health Initiative tracked breast cancer outcomes for more than 20 years after participants were randomized to receive either hormone therapy or placebo. The results showed strikingly different effects depending on the type of hormone therapy: estrogen alone (CEE) in women who had undergone hysterectomy was associated with 22% lower breast cancer incidence and 40% lower breast cancer mortality, while estrogen plus progestin (CEE plus MPA) in women with an intact uterus was associated with 28% higher breast cancer incidence but no significant difference in breast cancer mortality. These findings indicate that the addition of progestin to estrogen therapy substantially changes its impact on breast cancer risk, with estrogen-alone therapy appearing protective and estrogen-plus-progestin therapy increasing risk. The study helps resolve longstanding uncertainty about menopausal hormone therapy and breast cancer by demonstrating that the type of hormone therapy and whether a woman has had a hysterectomy are critical factors in determining breast cancer outcomes.

Use of hormone replacement therapy and risk of breast cancer: nested case-control studies using the QResearch and CPRD databases.

Vinogradova et al,

2020

Br Med J

A large UK study of 98,611 women with breast cancer and 457,498 controls found that long-term hormone replacement therapy (HRT) use (≥5 years) was associated with significantly increased breast cancer risk, with combined estrogen-progestogen therapy showing a 79% increased risk and estrogen-only therapy showing a 15% increased risk. Among combined therapies, norethisterone carried the highest risk (88% increase) while dydrogesterone showed the lowest (24% increase), and importantly, the increased risk from past long-term combined therapy use persisted even after stopping treatment (16% increased risk). In practical terms, recent combined HRT users could expect 9-36 extra breast cancer cases per 10,000 women per year depending on age, while estrogen-only users would see 3-8 extra cases per 10,000 women per year, providing critical information for women and clinicians weighing the benefits and risks of different HRT regimens.

Use of postmenopausal hormone therapies and risk of histology- and hormone receptor-defined breast cancer: results from a 15-year prospective analysis of NIH-AARP cohort.

Wang et al,

2020

Breast Cancer Res

A study of 118,760 postmenopausal women in the NIH-AARP cohort found that combined estrogen-progestogen therapy (EPT) was associated with a 54% increased breast cancer risk overall, with risk doubling for women using EPT for 10 or more years and reaching an 80% increased risk for those who continued use through 2004. Importantly, women who discontinued EPT showed no increased risk (14% non-significant increase), suggesting the elevated risk may be reversible after stopping treatment. Estrogen-only therapy (ET) showed no increased risk at baseline, though a 35% increased risk emerged in women who continued use through 2004, and EPT was associated with elevated risk across all breast cancer subtypes including in situ disease, invasive cancers, and tumors of varying hormone receptor status.

Night shift work and breast cancer: a pooled analysis of population-based case-control studies with complete work history.

Cordina-Duverger et al,

2018

Eur J Epidemiol

This large international study pooling data from over 13,000 women across five countries found that night shift work increased breast cancer risk by 26% in pre-menopausal women, with the risk rising substantially for those working longer shifts (≥10 hours), more frequent nights (≥3 nights per week), or longer durations (≥10 years). Pre-menopausal women working both long durations and high frequency had a 2.5 times higher breast cancer risk, with current or recent night workers at higher risk than those who had stopped more than two years ago. Notably, no increased risk was found in post-menopausal women, and the elevated risk was primarily for estrogen receptor-positive tumors, particularly those that were also HER2-positive, suggesting that disruption of hormones and circadian rhythms during reproductive years may be key factors in how night work affects breast cancer risk.

Prepubertal and Pubertal Endocrine-Disrupting Chemical Exposure and Breast Density among Chilean Adolescents.

Binder et al,

2018

Cancer Epidemiol Biomarkers Prev

This study examined how exposure to endocrine-disrupting chemicals (EDCs) during puberty affects breast tissue development in 200 Chilean girls by measuring urinary concentrations of phenols and phthalates at two stages of breast development and assessing breast density. The researchers found that certain phthalate metabolites were associated with increased breast density measures – specifically, higher levels of monocarboxyisooctyl phthalate were linked to 7% higher percent dense breast tissue, and monoethyl phthalate was associated with increased fibroglandular volume. Bisphenol A showed a U-shaped relationship with fibroglandular volume, where girls with middle-level exposures had at least 10% lower fibroglandular volume compared to those with low or high exposures. The findings suggest that developing breast tissue is vulnerable to certain EDCs during childhood and adolescence, which may have implications for future breast cancer risk since breast density is a known risk factor.

Breast cancer incidence after hormonal treatment for infertility: A meta-analysis of population-based studies.

Zaman et al,

2025

Saudi Med J

A systematic review and meta-analysis of 15 studies including 92,555 women found no evidence that hormonal fertility medications increase breast cancer risk, with pooled risk ratio analysis showing no association (RR=1.00, 95% CI: 0.97-1.02) and hazard ratio analysis initially suggesting a protective effect that became non-significant after accounting for study heterogeneity. The analysis revealed low heterogeneity in risk ratio studies but substantial heterogeneity in hazard ratio studies, which the authors attributed to methodological differences between studies rather than true variation in effects. These findings provide reassuring evidence for women considering or undergoing fertility treatment, though the authors caution that results should be interpreted carefully given the study heterogeneity and note that longer-term follow-up studies with standardized methodologies are needed to definitively establish the safety profile of hormonal fertility medications with respect to breast cancer risk, particularly for specific medication types, dosages, and treatment durations.

Exploring the reproductive exposure risks of phthalates and organophosphates in atmospheric particulate matter based on quantitative structure-activity relationships and network toxicology models.

Gao et al,

2025

J Hazard Mater

This study used advanced computer modeling to assess the combined reproductive health risks of phthalates (PAEs) and organophosphates (OPEs) found in atmospheric particles, focusing on their ability to disrupt hormone receptors. The researchers found that the mixed toxicity of these compounds was lower than expected from individual effects, suggesting they may interfere with each other’s toxic actions through antagonistic effects. Using network analysis and molecular modeling, they identified 590 potential targets and 50 core targets (including hormone receptors) affected by these pollutants, with DEHP, TPHP, and MEHP being key disruptors of hormone signaling pathways. The study also identified two previously overlooked targets (AKT1 and HSP90AA1) that may be important for reproductive toxicity, providing new insights into how these atmospheric pollutants may affect human reproductive health.

Evaluation of estrogenic and anti-estrogenic activity of endocrine disruptors using breast cancer spheroids: a comparative study of T47D and MCF7 cell lines in 2D and 3D models

Barbaro et al,

2025

Front Toxicol

The study examined the estrogenic and anti-estrogenic effects of three endocrine disruptors: Bisphenol A (BPA), which mimics estrogen, 17 -Estradiol (E2), the endogenous nuclear estrogen receptor ligand, and Fulvestrant (FUL), a drug that interferes with proper estrogen function. The experiment measured the influence of the endocrine disruptors in vitro using 2D and 3D T47D and MCF7 cells, which are estrogen receptor-positive human breast cancer cells. The study results concluded that E2 and BPA increased the expression of the estrogen-regulated marker pS2 and decreased TGF 3. Meanwhile, FUL inhibited E2 and BPA’s expression of the estrogen-regulated markers, meaning FUL reversed the effects of the other two endocrine disruptors.

Application of the Key Characteristics Framework to Identify Potential Breast Carcinogens Using Publicly Available in Vivo, in Vitro, and in Silico Data.

Kay et al,

2024

Environ Health Perspect

Researchers analyzed 279 chemicals known to cause mammary tumors in rodents and identified 642 additional chemicals that activate estrogen or progesterone signaling, finding that tumor-causing chemicals were significantly more likely to stimulate hormone production, activate estrogen receptors, or damage DNA—characteristics that likely increase breast cancer risk in humans. The study found that more mammary carcinogens worked by increasing hormone production than by directly activating estrogen receptors, with chemicals showing stronger hormone-disrupting effects being most likely to cause tumors, demonstrating a clear dose-response relationship. These findings suggest that hundreds of chemicals currently in use may pose unrecognized breast cancer risks and should not be assumed safe without specific testing for breast effects, with the strongest evidence chemicals prioritized for exposure reduction and improved testing methods needed to identify additional hazardous substances. The research provides a framework for identifying and regulating chemicals that may contribute to breast cancer through hormone disruption and genetic damage—mechanisms supported by both animal and human studies.

Assessing the impact of contraceptive use on reproductive cancer risk among women of reproductive age-a systematic review.

Jahanfar et al,

2024

Front Glob Women’s Health

A systematic review of 51 studies (2 RCTs and 49 observational studies) examined the association between modern contraceptive use and the risk of breast and reproductive cancers in women of reproductive age. The review found that hormonal contraceptive use significantly reduced the risk of ovarian cancer by 36% and endometrial cancer, while cervical cancer rates were lower among contraceptive users compared to non-users; notably, no increased breast cancer risk was found among healthy women (RR 1.00), but BRCA1/2 mutation carriers using oral contraceptives showed a 39% increased risk of breast cancer. These findings highlight the complex cancer-related effects of hormonal contraceptives: while they offer protective benefits against ovarian and endometrial cancers for most women, BRCA mutation carriers face elevated breast cancer risk, emphasizing the need for personalized contraceptive counseling that accounts for individual genetic risk factors. The study underscores the importance of healthcare providers considering family history and genetic profiles when discussing contraceptive options with women, particularly those with hereditary cancer susceptibility.

Endocrine disruptors: Unravelling the link between chemical exposure and Women’s reproductive health.

Hassan et al,

2024

Environ Res

Endocrine Disrupting Chemicals (EDCs)—including bisphenol A, phthalates, parabens, pesticides, and heavy metals commonly found in pharmaceuticals, cosmetics, and packaging—are widespread environmental pollutants that interfere with the body’s hormone system. Research shows EDCs have harmful effects on women’s reproductive health, contributing to conditions such as endometriosis, polycystic ovary syndrome, uterine fibroids, premature ovarian failure, menstrual irregularities, and infertility. This review emphasizes the need for healthcare professionals to consider environmental exposures when evaluating patients, highlights potential mechanisms by which EDCs affect female reproduction, and discusses how nutritional interventions and stricter environmental regulations could help reduce EDC-related health risks. Understanding the link between EDCs and women’s health is crucial for developing protective strategies, informing treatment approaches, and shaping public policies to safeguard reproductive and overall well-being. The study seeks to advise that couples attempting to conceive should avoid endocrine disrupting chemicals (EDCs) such as BPA, pesticides, and phthalates. Following this advice is found to be crucial during the prenatal and periconceptional periods, where fetal development and growth are critical in this window.

Associations of Circulating Estrogens and Estrogen Metabolites with Fecal and Oral Microbiome in Postmenopausal Women in the Ghana Breast Health Study.

Wu et al,

2023

Microbiol Spectr

Gut Health| Hormones| Human| Mechanistic Studies| Microbiome

A study of 117 postmenopausal African women found significant links between blood levels of estrogens (hormones associated with breast cancer risk) and the composition of bacteria in both the gut and mouth. Higher levels of certain estrogens were associated with greater diversity of gut bacteria, while specific estrogen byproducts were linked to differences in oral bacteria composition, including bacterial families known to help metabolize estrogens. These findings suggest that gut and oral bacteria may influence breast cancer risk by affecting how the body processes estrogens, though larger studies are needed to confirm how these relationships develop over time.

Exposure to pesticides and breast cancer in the city of Petrópolis, Brazil.

de Rezende et al,

2023

Environ Sci Pollut Res

A hospital-based case-control study in Petrópolis, Brazil found that women exposed to pesticides for 10 or more years had elevated but non-significant breast cancer risk after adjusting for confounders (OR = 1.40; 95% CI: 0.85-2.49), while higher education and hormone replacement therapy showed significant positive associations, and having 2+ pregnancies was protective. The authors conclude that further research is needed to clarify pesticide exposure’s contribution to breast cancer development given conflicting findings in the literature.

Bisphenols and alternative developers in thermal paper receipts from the U.S. market assessed by Fourier transform infrared spectroscopy.

Miller et al,

2023

Environ Pollut

A 2022 study tested 571 cash register receipts from U.S. retailers to assess endocrine-disrupting chemicals in thermal paper and compared findings to a 2017 study. Bisphenol S (BPS) was found in 85% of receipts, Pergafast 201 in 12%, and bisphenol A (BPA) in only 1%, indicating a shift away from BPA. National retailers were more likely than local ones to use non-bisphenol alternatives. These findings highlight potential health risks from handling receipts, as BPS and other chemicals can still pose significant exposure concerns.

Endocrine-disrupting chemicals and breast cancer: a meta-analysis.

Liu et al,

2023

Frontiers

This meta-analysis aimed to evaluate the association between exposure to endocrine-disrupting chemicals (EDCs), including phthalates and other common environmental pollutants, and breast cancer risk. The study found that certain EDCs—such as p,p′-DDT, chlordane, HCH, and specific PCBs—were positively associated with increased breast cancer risk, while a few compounds like BBP and PFDoDA showed a negative association.

A simple and fast multiclass method for determination of steroid hormones in berry fruits, root and leafy vegetables

Merlo et al,

2022

Talanta Open

Hormones| Food| Cellular/Molecular/Tissue| Hormones| Hormones

This study developed a sensitive analytical method to detect steroid hormones (progestins, estrogens, androgens, and glucocorticoids) in fruits and vegetables, using strawberry, carrot, and spinach as test samples. The optimized extraction procedure uses ultrasonic extraction with minimal methanol, followed by clean-up and analysis via HPLC-ESI-MS/MS, achieving good recoveries at concentrations of 10-50 ng/g. The method was successfully applied to additional produce (raspberry, radish, arugula) and used to analyze market-purchased samples, where some steroids were detected at low ng/g levels. These findings are consistent with existing literature on steroid hormone accumulation in edible plants as emerging environmental pollutants.

Molecular consequences of the exposure to toxic substances for the endocrine system of females.

Kowalczyk et al,

2022

Biomed Pharmacother

A review of endocrine-disrupting chemicals (EDCs)—ubiquitous substances found in cosmetics, plastic food packaging, and medicines that enter the body through skin, digestive, or respiratory routes—examined their toxic effects even at microgram doses on the female reproductive system and genetic mechanisms. EDCs disrupt endocrine functions by binding to steroid hormone receptors, interfering with hormone synthesis and secretion, and modulating epigenetic processes that can lead to gene expression disturbances, contributing to neoplastic diseases, neurological disorders, circulatory problems, and reproductive dysfunction. Prenatal exposure can affect offspring development, with particular impacts on ovarian function leading to reduced fertility through disturbances in steroid receptor function, steroidogenesis, and gametogenesis. The review emphasizes that despite widespread exposure to these chemicals in everyday products, continued research is needed to fully understand their effects on the female reproductive system and potential transgenerational impacts mediated through epigenetic mechanisms.

Endocrine disrupting chemicals and breast cancer: a systematic review of epidemiological studies.

Wan et al,

2022

Crit Rev Food Sci Nutr

This systematic review of 131 epidemiological studies evaluated the association between various endocrine-disrupting chemicals, including phthalates and hormonal exposures like contraceptive pills, and the risk of breast cancer. It found that several EDCs, particularly phthalates and oral contraceptive use, were consistently associated with increased breast cancer risk across multiple studies.

Oral Contraceptive Use and Breast Cancer Risk According to Molecular Subtypes Status: A Systematic Review and Meta-Analysis of Case-Control Studies.

Barańska et al,

2022

Cancers

A meta-analysis of 19 case-control studies found that oral contraceptive (OC) use had markedly different effects on breast cancer risk depending on tumor receptor status: OC use was associated with a 37% increased risk of triple-negative breast cancer and a 20% increased risk of ER-negative breast cancer, while showing an 8% reduced risk of ER-positive breast cancer and a non-significant 5% reduced risk of HER2-positive breast cancer. These contrasting associations suggest that oral contraceptives may influence breast cancer development through different biological mechanisms depending on tumor subtype, with particularly concerning implications for triple-negative breast cancer—the most aggressive subtype with limited treatment options. The findings highlight the importance of considering breast cancer heterogeneity when evaluating hormonal contraceptive risks and suggest that women at high risk for triple-negative or ER-negative breast cancer may need alternative contraceptive counseling.

Oral contraceptives and risk of breast cancer and ovarian cancer in women with a BRCA1 or BRCA2 mutation: a meta-analysis of observational studies.

Park et al,

2022

Carcinogen

A meta-analysis of 12 breast cancer studies and 8 ovarian cancer studies in women with BRCA1 or BRCA2 mutations found that oral contraceptive (OC) use was associated with a 24% increased breast cancer risk but a 47% decreased ovarian cancer risk. The increased breast cancer risk was observed only with long-term OC use (>5 years), while the ovarian cancer protection occurred regardless of duration, and these patterns were consistent when BRCA1 and BRCA2 carriers were analyzed separately. These findings present a complex risk-benefit trade-off for BRCA mutation carriers considering oral contraceptives, suggesting that while OCs provide substantial protection against ovarian cancer—a particularly deadly cancer in this high-risk population—they also modestly increase breast cancer risk with prolonged use, requiring careful individualized counseling about contraceptive choices and cancer prevention strategies.

Association between fertility treatments and breast cancer risk in women with a family history or BRCA mutations: a systematic review and meta-analysis.

Liu et al,

2022

Front Endocrinol

A meta-analysis of 8 studies (5 cohort and 3 case-control studies) examined whether fertility treatments increase breast cancer risk in genetically susceptible women, including those with a family history of breast cancer or BRCA mutations. The analysis found no significant increase in breast cancer risk associated with fertility treatments in genetically susceptible women overall (OR 1.18), women with a family history of breast cancer (OR 1.35), or BRCA mutation carriers (OR 1.02), with similarly reassuring results across subgroups including BRCA1 carriers, BRCA2 carriers, and women treated with specific fertility medications like in vitro fertilization, clomiphene citrate, or gonadotropins. This first meta-analysis on this topic provides reassuring evidence that fertility treatments do not significantly increase breast cancer risk even in women with hereditary susceptibility, though the authors note that larger prospective studies with more detailed information are needed to fully understand potential risks. Future research should examine whether risks vary by breast cancer subtype, explore the genetic mechanisms underlying hormone-related breast cancer, and investigate the relationship between BRCA mutations and hormone receptor-positive breast cancer specifically.

A sensitive environmental forensic method that determines bisphenol S and A exposure within receipt-handling through fingerprint analysis.

Jang et al,

2022

J Hazard Mater

This study investigates human exposure to bisphenol A (BPA) and bisphenol S (BPS) by handling thermal paper receipts. The study analyzed the BPS and BPA concentrations from the fingerprints of individuals who handled thermal paper receipts and compared them to those of people who didn’t handle thermal paper receipts. The results found that 20–40 μg of BPS or BPA is transferred to human skin as seen through the fingerprint after contact with thermal papers containing 100–300 μg. Additionally, the transfer of BPA was 2.9–5.2 times higher than BPS, which is consistent with higher concentrations in receipts. However, washing hands significantly reduced the transfer of both BPS and BPA. This is important because the study also determined lipid metabolism was affected at concentrations greater than 10 mg/L. Additionally, it had adverse effects on the growth of water flees, indicating that it may potentially have some effect on human development as well.

Environmental endocrine disruptor concentrations in urine samples from Mexican Indigenous women.

Rodríguez-Báez et al,

2022

Environ Sci Pollut Res

The following study explores the presence of endocrine disruptors such as phthalates (specifically mono-2-ethyl phthalate and mono-n-butyl phthalate), bisphenol A (BPA), and 1-hydroxypyrene in the urine samples of marginalized Indigenous populations. The study found that 100% of the women sampled showed exposure to these harmful chemicals, with higher concentrations than observed in similar studies from other communities. This increased exposure is linked to environmental and cultural factors, such as the common use of plastic containers and practices such as burning garbage. The women sampled were found to have especially high levels of mono-2-ethyl phthalate, which suggests significant exposure to di(2-ethylhexyl) phthalate. These findings highlight the vulnerability of indigenous communities to pollution due to a lack of awareness, limited healthcare access, and inadequate regulatory measures.

Biodegradable polymers and their nano-composites for the removal of endocrine-disrupting chemicals (EDCs) from wastewater: A review

Sharabati et al,

2021

Environ Res

Biodegradable polymers are emerging as a promising solution for removing endocrine-disrupting chemicals (EDCs) from wastewater. EDC’s, found in pharmaceuticals, pesticides, and personal care products pose serious health risks, impacting the endocrine system and disrupting reproductive health. Traditional water treatments often fail to fully remove EDCs. Biodegradable polymers, with strong adsorptive properties, offer a sustainable and effective method, helping to minimize EDC exposure and protect human and environmental health.

Endocrine disrupting chemicals and breast cancer cells.

Darbre et al,

2021

Adv Pharmacol

A comprehensive review examining endocrine-disrupting chemicals (EDCs) in breast tissue concludes that hundreds of these environmental chemicals are entering human breast tissue and contributing to the global rise in breast cancer incidence through multiple biological mechanisms. Laboratory studies demonstrate that EDCs can activate all the established “hallmarks of cancer” in human breast cancer cells—even at concentrations measured in actual human breast tissue—with effects amplified when chemicals are present as mixtures rather than individually. The authors argue that EDCs must now be formally recognized as a breast cancer risk factor to enable prevention strategies that include reducing environmental chemical exposures, particularly given that the varied mixtures of EDCs found in individual breast tissues act through overlapping mechanisms to promote cancer development.

Mediation analysis of the alcohol-postmenopausal breast cancer relationship by sex hormones in the EPIC cohort.

Assi et al,

2020

Int J Cancer

A nested case-control study within a large European cohort of 430 breast cancer cases and 645 controls found that while alcohol consumption was associated with a 17% increased overall breast cancer risk (36% for ER-positive tumors), individual sex hormones showed limited evidence of mediating this relationship except for a weak effect through free estradiol. However, when researchers used a sophisticated statistical approach (partial least squares regression) to create an alcohol-related hormonal signature—characterized by lower SHBG and higher estradiol and testosterone—this hormonal pattern was associated with 25% increased breast cancer risk and mediated approximately 24% of the alcohol-breast cancer association. These findings suggest that alcohol increases breast cancer risk partly through a complex hormonal mechanism involving the interplay of multiple sex hormones rather than through individual hormones alone, providing new mechanistic insight into how alcohol consumption drives breast carcinogenesis in postmenopausal women and supporting recommendations to limit alcohol intake for breast cancer prevention.

Relationship between Night Shifts and Risk of Breast Cancer among Nurses: A Systematic Review.

Fagundo-Rivera et al,

2020

Medicina

A systematic review of 12 studies examining nurses and shift work found that most studies showed an association between breast cancer and consecutive rotating night shifts prolonged over time, with risk increasing particularly during early adulthood and after 5 or more years of working 6 or more consecutive night shifts. The review identified disruption of circadian rhythm and alterations in peripheral clock genes and reproductive hormones as key mechanisms linking night shift work to breast cancer development, with potential roles for melatonin suppression and epigenetic changes including telomere alterations. These findings are particularly concerning given that nursing is a predominantly female profession requiring 24-hour staffing, suggesting the need for workplace policies that limit consecutive night shifts and total years of night work exposure, along with further research to establish definitive causal mechanisms and identify protective strategies for the millions of women working night shifts globally.

The Gut Microbiota: A Potential Gateway to Improved Health Outcomes in Breast Cancer Treatment and Survivorship.

Sampsell et al,

2020

Int J Mol Sci

The gut microbiome—trillions of bacteria living in the digestive tract—appears to influence breast cancer risk, treatment effectiveness, and likelihood of recurrence through its effects on metabolism, hormones, immune function, and brain signaling. While cancer treatments can disrupt the gut microbiome and contribute to negative side effects, research shows that the microbiome can be positively modified through diet, probiotic and prebiotic supplements, and exercise. This review synthesizes current evidence on the gut-breast cancer connection and highlights practical strategies for improving gut health that may lead to better treatment outcomes, fewer side effects, and improved overall wellbeing for breast cancer patients.

Environmental exposures and breast cancer risk in the context of underlying susceptibility: A systematic review of the epidemiological literature.

Zeinomar et al,

2020

Environ Res

A systematic review of 100 publications across 56 epidemiologic studies found that research enriched with women at higher baseline breast cancer risk—through family history, early-onset disease, or genetic susceptibility—consistently showed stronger and more frequent associations between environmental chemical exposures and breast cancer compared to average-risk populations. Specifically, 80% of studies enriched with family history or early-onset cases showed significant associations with exposures including PAHs, air pollution, DDT, PCBs, PFAS, metals, personal care products, and occupational chemicals, while 74% of studies examining genetic susceptibility found significant gene-environment interactions for various pollutants in women with variants affecting carcinogen metabolism, DNA repair, and oxidative stress. These findings suggest that the inconsistent evidence for environmental chemicals and breast cancer in the literature may partly stem from studying predominantly average-risk populations who may be less susceptible to environmental carcinogens, highlighting the critical need for future research to focus on high-risk populations and measure exposures during key windows of susceptibility (puberty, pregnancy, menopause) to more accurately capture the role of environmental chemicals in breast cancer development.

Food advanced glycation end products as potential endocrine disruptors: An emerging threat to contemporary and future generation.

Ravichandran et al,

2019

Environ Int

Advanced glycation end products (AGEs), formed during the processing of foods at high temperatures, act as endocrine disruptors and are linked to various health risks. These compounds accumulate in the body over time, promoting oxidative stress, aging, diabetes, and other degenerative diseases. Processed foods, often convenient and inexpensive, are significant sources of AGEs, contributing to hormonal disruption and potential long-term health effects. Choosing minimally processed, whole foods can help reduce exposure to these harmful compounds and support overall hormonal balance, reinforcing the importance of food quality in maintaining long-term health and well-being.

Effect of age at first use of oral contraceptives on breast cancer risk: An updated meta-analysis.

Ji et al,

2019

Medicine

A meta-analysis of 10 studies including 8,585 breast cancer cases among 686,305 participants examined the relationship between age at first oral contraceptive (OC) use and breast cancer risk through June 2018. The pooled analysis found a 24% increased breast cancer risk associated with earlier age at first OC use (RR = 1.24; 95% CI: 1.10-1.41), with a significant linear dose-response relationship indicating that younger age at first use was associated with higher breast cancer risk. However, subgroup analyses showed inconsistent results with no statistical significance when restricted to studies from Western countries, lower quality studies, smaller sample sizes, shorter follow-up periods, or when stratified by breast cancer subtypes defined by estrogen receptor (ER), progesterone receptor (PR), or HER2 status. The findings suggest that starting oral contraceptive use at a younger age may increase breast cancer risk in a dose-dependent manner, though this association appears to be influenced by study characteristics and may not differ consistently across hormone receptor-defined breast cancer subtypes, highlighting the need for further research to clarify these relationships and inform contraceptive counseling for young women.

The effects of bisphenol A, benzyl butyl phthalate, and di(2-ethylhexyl) phthalate on estrogen receptor alpha in estrogen receptor-positive cells under hypoxia.

Park et al,

2019

Environ Pollut

This study investigated how three endocrine-disrupting chemicals (BPA, BBP, and DEHP) affect estrogen receptor alpha (ERα) activity under normal and low-oxygen (hypoxic) conditions in breast and endometrial cancer cells. The researchers found that BPA and BBP activated ERα at specific concentrations, while DEHP did not, but all three chemicals enhanced ERα-mediated gene activity and decreased ERα protein levels under hypoxic conditions. BPA and BBP also affected hypoxia-related factors, decreasing hypoxia-inducible factor-1 activity while increasing VEGF (a blood vessel growth factor) secretion in breast cancer cells, whereas DEHP had different effects. The findings suggest that these endocrine disruptors can alter ERα regulation under low-oxygen conditions, which may influence disease processes since hypoxia is common in tumors and other pathological states.

Bisphenol AF promotes estrogen receptor-positive breast cancer cell proliferation through amphiregulin-mediated crosstalk with receptor tyrosine kinase signaling.

Zhao et al,

2019

PLOS One

Bisphenol AF (BPAF)—a chemical increasingly used to replace BPA in consumer products—shows even stronger estrogen-like effects than BPA and promotes the growth of estrogen receptor-positive (ER+) breast cancer cells through multiple hormone signaling pathways. Laboratory studies revealed that BPAF stimulates cancer cell proliferation by activating estrogen receptors and upregulating AREG, a growth-promoting gene, with blocking either estrogen receptors or AREG preventing BPAF’s cancer-promoting effects. These findings challenge the assumption that BPA alternatives are safer, demonstrating that BPAF may pose equal or greater breast cancer risks than the chemical it’s replacing, and highlight the urgent need for human studies to assess BPAF’s impact on breast cancer risk before its continued widespread use in products marketed as “BPA-free.”

Obesity as risk factor for subtypes of breast cancer: results from a prospective cohort study.

Nattenmüller et al,

2018

BMC Cancer

A prospective analysis of 657 incident breast cancer cases from the EPIC-Germany Study (n=27,012) with immunohistochemical characterization of tumors by six markers (ER, PR, HER2, Ki67, Bcl-2, p53) found that among postmenopausal women not using hormone therapy (HT), higher BMI was significantly associated with increased risk of less aggressive tumors characterized by ER+, PR+, HER2-, low Ki67, Bcl-2+, and p53- status (HR per 5 kg/m²: 1.44; 95% CI: 1.10-1.90) but not more aggressive subtypes, while among postmenopausal HT users, BMI showed a significant inverse association with less aggressive tumors (HR per 5 kg/m²: 0.68; 95% CI: 0.50-0.94). Among pre- and perimenopausal women, no significant linear associations emerged, though the highest BMI tertile showed significantly lower risk of less aggressive tumors (HR: 0.55; 95% CI: 0.33-0.93). These findings suggest that obesity’s relationship with breast cancer is highly nuanced, being associated with increased risk of less aggressive, hormone-responsive tumors in postmenopausal women not using HT, paradoxically protective in HT users and younger women, highlighting the complex interplay between adiposity, endogenous and exogenous hormones, menopausal status, and tumor biology that requires replication in larger pooled prospective studies.

Menopausal hormone therapy and the risk of breast cancer by histological type and race: a meta-analysis of randomized controlled trials and cohort studies.

Kim et al,

2018

Breast Cancer Res Treat

A meta-analysis of 25 epidemiological studies (23 cohort studies and 2 randomized trials) found that hormone replacement therapy (HRT) was associated with a 33% increased breast cancer risk overall, with combined estrogen-progestin therapy (EPT) showing stronger associations than estrogen-only therapy (ET). EPT was associated with both ductal (51% increased risk) and lobular breast cancer (38% increased risk), and all HRT types were linked to ER-positive but not ER-negative breast cancers, consistent with hormone-driven carcinogenesis. Notably, Asian women using HRT showed higher breast cancer risk than Western women, possibly due to differences in baseline hormone levels, genetic susceptibility, body composition, or HRT formulations used—a finding highlighting the importance of considering racial and ethnic differences when counseling women about menopausal hormone therapy risks and benefits.

Menopausal Hormone Therapy use and breast cancer risk by receptor subtypes: Results from the New South Wales Cancer Lifestyle and EvaluAtion of Risk (CLEAR) study.

Salagame et al,

2018

PLOS One

A case-control study of 399 breast cancer patients with receptor status information and 324 controls found that current menopausal hormone therapy (MHT) use was associated with approximately double the risk of hormone receptor-positive breast cancers, including ER+ (104% increased risk), ER+/PR+ (129% increased risk), and notably ER+/PR+/HER2- subtypes (130% increased risk). Past MHT use showed no elevated risk for any subtype, and current use was not significantly associated with hormone receptor-negative cancers, indicating the effect is specific to hormonally-driven tumors. These findings provide mounting evidence that MHT specifically increases risk of the ER+/PR+/HER2- subtype—the most common breast cancer type—adding to concerns about current hormone therapy use and supporting the need for women and clinicians to carefully weigh the duration of MHT treatment against cardiovascular and quality-of-life benefits versus breast cancer risks.

Disruptive environmental chemicals and cellular mechanisms that confer resistance to cell death.

Narayanan et al,

2015

Carcinogenesis

This study explores the linkage between environmental chemical exposures and cellular resistance to cell death, a carcinogenic trait. The researchers in this study specifically investigate BPA, chlorothalonil, dibutyl phthalate, and more because of their disruptive effects that may be involved in these carcinogenic pathways. The researchers found that arsenic interferes with cellular signaling pathways and induces oxidative stress, leading to impaired apoptosis; dioxins bind to aryl hydrocarbon receptors (AHRs), which alters gene expression and disrupts normal cell death processes; BPA mimics the estrogen hormone, affecting hormonal balance and promoting cell survival pathways that inhibit cell death. By allowing cells to evade cell death, these environmental chemicals can promote the survival of cells with genetic mutations and therefore increase the risk of cancer development.

Effects of Low-Dose Bisphenol A on DNA Damage and Proliferation of Breast Cells: The Role of c-Myc.

Pfeifer et al,

2015

Environ Health Perspect

This study investigates how low concentrations of Bisphenol A (BPA) affect DNA integrity and cell proliferation in breast cells, focusing on the involvement of the oncogene c-Myc. They found that exposure to low doses of BPA resulted in significant DNA damage in estrogen receptor-alpha (ERα)-negative mammary cells, meaning that BPA can promote cancer in ways independent of standard estrogen receptor pathways. Additionally, BPA exposure led to the upregulation of c-Myc, which is a gene known to regulate cell proliferation and death., and the study did observe enhanced proliferation of ERα-negative mammary cells upon BPA exposure. This suggests that BPA may promote cancer pathways through c-Myc activation. This was then confirmed when the researchers silenced c-Myc gene expression and found that oncogenic effects in the presence of BPA were decreased. Overall, these findings raise concerns about BPA’s potential role in breast cancer formation, even at low exposure levels.

Early-life Exposure to Endocrine Disrupting Chemicals and Later-life Health Outcomes: An Epigenetic Bridge?

Vaiserman et al,

2014

Aging Dis

The following review article described how exposure to EDCs during early development can lead to adverse health outcomes later in life through epigenetic mechanisms based on existing studies. The article emphasizes that exposure to EDCs during critical developmental periods such as in utero and early childhood, can have lasting effects on health since, during these periods, the body’s systems are particularly vulnerable to exposures. Additionally, the article finds a link between early-life exposure to EDCs and increased risk of various health issues later on in life, including metabolic disorders and cancers. The suspected mechanism by which these chemicals do this is thought to be mediated by epigenetic changes, which are changes to gene expression without altering the DNA. Therefore, the article emphasizes understanding how exposure during such sensitive periods in development can pose such drastic problems later on in life.

Designing Endocrine Disruption Out of the Next Generation of Chemicals.

Schug et al,

2013

Green Chemistry

Scientists have developed TiPED (Tiered Protocol for Endocrine Disruption), a voluntary five-tier testing system designed to help chemists identify hormone-disrupting properties in new chemicals during the design phase—before they enter consumer products—ranging from computer-based predictions to cell and animal studies. The protocol was created by experts in green chemistry and environmental health to broadly test whether new chemicals can mimic or block hormones or interfere with hormone signaling, which is critical for preventing endocrine disruption that can contribute to diseases like breast cancer. Testing of six known endocrine disruptors with different mechanisms of action successfully identified all of them, demonstrating the protocol’s effectiveness, though the system will continue evolving as scientific understanding advances. This tool represents an important shift toward preventing chemical hazards at the design stage rather than discovering them years later after widespread human exposure, which could significantly reduce public health risks including breast cancer.

Endocrine disruptors and asthma-associated chemicals in consumer products.

Dodson et al,

2012

Environ Health Perspect

This study analyzed 213 everyday products, including cosmetics, cleaners, and personal care items, for endocrine-disrupting chemicals (EDCs) and asthma-related compounds. Testing revealed 55 chemicals, with fragranced products and sunscreens containing the highest levels. Vinyl products were also found to contain significant amounts of bis(2-ethylhexyl) phthalate (DEHP), a known EDC. Many harmful chemicals were not listed on product labels, limiting consumer ability to avoid them. These results highlight the presence of potentially harmful chemicals in commonly used products, raising concerns about their widespread use in household and personal care items.

Bisphenol A: an endocrine disruptor with widespread exposure and multiple effects.

Rubin et al,

2011

J Steroid Biochem Mol Biol

Bisphenol A (BPA) is a widely produced chemical used in plastics and food container linings, with frequent human exposure due to its leaching into food and beverages. BPA, a known endocrine disruptor, was initially deemed a weak estrogen but has shown potency comparable to estradiol, a form of estrogen, shown to affect multiple hormonal pathways. Studies on rodents reveal adverse effects at levels below and at the current acceptable daily intake, raising concerns about human health impacts about concentration. BPA’s estrogenic effects highlight the importance of investigating BPA’s complex, widespread impacts on health.

Environmental pollutants and breast cancer: epidemiologic studies.

Brody et al,

2007

Cancer

A comprehensive review found that while laboratory studies have identified numerous environmental chemicals that cause breast tumors in animals or mimic estrogen, human epidemiological evidence is strongest for PAHs (found in air pollution and grilled foods) and PCBs (banned industrial chemicals), particularly in women with certain genetic variations affecting how their bodies process these chemicals and hormones. Evidence linking dioxins and organic solvents to breast cancer is limited but suggestive, while many chemicals identified as mammary carcinogens in animal studies have never been investigated in human populations due to challenges in measuring past exposures and the decades-long delay between exposure and cancer diagnosis. The review argues that given these methodological limitations in human studies, policymakers should rely more heavily on animal and laboratory evidence to develop regulations that reduce chemical exposures, as waiting for definitive human proof may unnecessarily delay prevention strategies that could reduce breast cancer rates.

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