Cytotoxic T cell depletion with increasing epithelial abnormality in women with benign breast disease.

PURPOSE: We quantified cytotoxic T cells in nonmalignant breast tissues from women with and without subsequent breast cancer to assess evidence of whether immunosurveillance may be suppressed prior to tumor development. METHODS: We used an age-matched set of breast tissues from women with benign breast disease (BBD) who subsequently developed breast cancer (BBD with later BC), women with BBD who remained cancer free (BBD cancer-free), and normal Komen Tissue Bank (KTB) tissue donors (KTB controls). We evaluated terminal duct lobular units (lobules) for degree of epithelial abnormality and density of dual-positive CD8/CD103 T cells, as CD103+ cells are thought to be a subset of CD8+ cytotoxic T cells located primarily in the intraepithelial compartment. RESULTS: In 10 sets of age-matched women, 256 breast lobules were studied: 85 in BBD women with later BC, 85 in BBD cancer-free women, and 86 in KTB donors. The majority of all lobules were histologically normal (N = 143, 56%), with 65 (25%) nonproliferative fibrocystic change, and 48 (19%) proliferative epithelial change (with or without atypia). In BBD women with later BC, median CD8+/CD103+ cell density was 39.6, 31.7, and 10.5 cells/mm2 (p = 0.002) for normal, nonproliferative, and proliferative lobules. In BBD cancer-free women, median CD8+/CD103+ cell density values were 46.7, 14.3, and 0 cells/mm2 (p = 0.004) respectively. In KTB donors, CD8+/CD103+ cell density was not significantly different across the lobule types (medians 0, 5.8, 10.7, p = 0.43). CONCLUSION: In women with BBD, breast lobules with increasing epithelial abnormality show significant decreases in cytotoxic T cells as measured by CD8/CD103 staining, suggesting that impaired immunosurveillance may be a component of the earliest stages of breast cancer development.

Barriers and opportunities for breast cancer organizations to focus on environmental health and disease prevention: a mixed-methods approach using website analyses, interviews, and focus groups.

BACKGROUND: Breast cancer is the most commonly diagnosed cancer among women worldwide and most cases are not due to high risk inherited genes. In response, breast cancer activists successfully advocated for innovative research on environmental chemical exposures as a possible cause. Since then, new evidence supports hypotheses that common industrial and consumer chemicals are linked to the disease, and expert panels recommend reducing exposures. We evaluated whether these research results and recommendations are translated back into the work of breast cancer organizations and what barriers and opportunities influence their ability to focus on environmental factors. METHODS: We used a Python script to evaluate the frequency of environmental terms on the websites of 81 breast cancer organizations (> 14,000 associated URLs) and conducted two focus groups and 20 interviews with leaders of breast cancer organizations. We also analyzed the frequency of terms on two trusted, national cancer websites. RESULTS: 40% of organizations include information on environmental chemicals on their websites, but references are infrequent and rarely cite specific chemicals of concern. Most organizations (82%) discuss other risk factors such as exercise, diet, family history, or genetics. From interviews and focus groups, we identified four types of barriers to addressing environmental chemicals: 1) time and resource constraints, 2) limited knowledge of the state of the research and lack of access to experts, 3) difficulties with messaging, including concern that cultural and economic factors make it difficult for individuals to reduce their exposures, and 4) institutional obstacles, such as the downplaying of environmental risks by industry interests. Participants expressed the desire for easy-to-adopt educational programs and increased federal funding for scientist-advocate research partnerships. CONCLUSION: Our research underscores the need for environmental breast cancer experts and trusted cancer organizations to increase research translation activities so that breast cancer organizations can communicate new science on environmental factors in their online and in-person work. Moreover, our research highlights how most groups are focusing on providing resources to diagnosed women, including addressing problems with healthcare access, which displaces their ability to work on breast cancer prevention.

Exploring Challenges Related to Breast Cancer to Identify Opportunities for Advocacy in Hawassa City, Southern Ethiopia: A Community-Based, Qualitative Study.

PURPOSE: The aim of this study was to explore breast cancer (BC) challenges to identify opportunities for advocacy in southern Ethiopia in 2022. METHODS: Twenty-five participants from four local districts (kebeles) in Hawassa City were selected as key contributors to future work. Semistructured in-depth interviews were held for two clinicians, two local health bureau managers, two media managers, and three religious leaders. Two focus group discussions were conducted: one included six BC survivors and a caregiver; the other included two health extension workers, three members of the Women's Development Group, two community volunteers, one kebele leader, and one traditional healer. RESULTS: To our knowledge, our study was the first time that most participants had assembled. Many referred to patients as victims and BC as a killer disease or curse. Community and religious leaders were concerned about challenges and willing to collaborate. Survivors, providers, and religious leaders were identified as key sources of information, positive messages, and leadership. CONCLUSION: Recommendations for advocacy work in Hawassa include lobbying for BC as a health priority; including BC within the health extension package; initiating programs for earlier detection; educating the community to remove stigmas of the disease and treatments; working with media to disseminate messages that are inclusive of people in remote areas and speaking different languages; improving availability, affordability, and access to care; and assisting patients with psychosocial support. A strategic collaboration between religious leaders and health care providers was identified to increase community awareness and support advocacy for patients.

Methylation biomarkers of polybrominated diphenyl ethers (PBDEs) and association with breast cancer risk at the time of menopause.

BACKGROUND: Exposure to polybrominated diphenyl ethers (PBDEs) may influence risk of developing post-menopausal breast cancer. Although mechanisms are poorly understood, epigenetic regulation of gene expression may play a role. OBJECTIVES: To identify DNA methylation (DNAm) changes associated with PBDE serum levels and test the association of these biomarkers with breast cancer risk. METHODS: We studied 397 healthy women (controls) and 133 women diagnosed with breast cancer (cases) between ages 40 and 58 years who participated in the California Teachers Study. PBDE levels were measured in blood. Infinium Human Methylation EPIC Bead Chips were used to measure DNAm. Using multivariable linear regression models, differentially methylated CpG sites (DMSs) and regions (DMRs) associated with serum PBDE levels were identified using controls. For top-ranked DMSs and DMRs, targeted next-generation bisulfite sequencing was used to measure DNAm for 133 invasive breast cancer cases and 301 age-matched controls. Conditional logistic regression was used to evaluate associations between DMSs and DMRs and breast cancer risk. RESULTS: We identified 15 DMSs and 10 DMRs statistically significantly associated with PBDE levels (FDR < 0.05). Methylation changes in a DMS at BMP8B and DMRs at TP53 and A2M-AS1 were statistically significantly (FDR < 0.05) associated with breast cancer risk. CONCLUSION: We show for the first time that serum PBDE levels are associated with differential methylation and that PBDE-associated DNAm changes in blood are associated with breast cancer risk.

Molecular Mechanisms of Polybrominated Diphenyl Ethers (BDE-47, BDE-100, and BDE-153) in Human Breast Cancer Cells and Patient-Derived Xenografts.

Polybrominated diphenyl ethers (PBDEs) have been used as flame retardants in household materials. Their environmental persistence has led to continuous human exposure and significant tissue levels. Three PBDE congeners (BDE-47, BDE-100, and BDE-153) have been frequently detected in human serum. Although these compounds appear to possess endocrine disrupting activity, studies are largely missing to determine the biological mechanisms of PBDEs in breast cancer cells. Here, we assessed PBDE bioactivities with three complementary strategies: receptor binding/activity assays; nonbiased RNA-sequencing analysis using an estrogen-dependent breast cancer cell line MCF-7aroERE; and in vivo assessments using patient-derived xenograft (PDX) models of human breast cancer. According to the results from in vitro experiments, the PBDE congeners regulate distinct nuclear receptor signaling pathways. BDE-47 acts as a weak agonist of both estrogen receptor α (ERα) and estrogen-related receptor α (ERRα); it could stimulate proliferation of MCF-7aroERE and induced expression of ER-regulated genes (including cell cycle genes). BDE-153 was found to act as a weak antagonist of ERα. BDE-100 could act as (1) an agonist of aryl hydrocarbon receptor (AhR), inducing expression of CYP1A1 and CYP1B1 and (2) as a very weak agonist/antagonist of ERα. In vivo, a mixture of the three congeners with ratios detected in human serum was tested in an ER+ PDX model. The mixture exhibited estrogenic activity through apoptosis/cell cycle regulation and increased the expression of a proliferation marker, Ki-67. These results advance our understanding of the mechanisms of PBDE exposure in breast cancer cells.

Single-cell RNA-sequencing analysis of estrogen- and endocrine-disrupting chemical-induced reorganization of mouse mammary gland.

Menopause is a critical window of susceptibility for its sensitivity to endocrine disrupting chemicals due to the decline of endogenous estrogen. Using a surgical menopausal (ovariectomized) mouse model, we assessed how mammary tissue was affected by both 17ß-estradiol (E2) and polybrominated diphenyl ethers (PBDEs). As flame retardants in household products, PBDEs are widely detected in human serum. During physiologically-relevant exposure to E2, PBDEs enhanced E2-mediated regrowth of mammary glands with terminal end bud-like structures. Analysis of mammary gland RNA revealed that PBDEs both augmented E2-facilitated gene expression and modulated immune regulation. Through single-cell RNA sequencing (scRNAseq) analysis, E2 was found to induce Pgr expression in both Esr1+ and Esr1- luminal epithelial cells and Ccl2 expression in Esr1+ fibroblasts. PBDEs promote the E2-AREG-EGFR-M2 macrophage pathway. Our findings support that E2 + PBDE increases the risk of developing breast cancer through the expansion of estrogen-responsive luminal epithelial cells and immune modulation.