Epigenetic Mechanisms of Endocrine-Disrupting Chemicals in Breast Cancer and Their Impact on Dietary Intake

Abstract

Addressing the consequences of exposure to endocrine-disrupting chemicals (EDCs) demands thorough research and elucidation of the mechanism by which EDCs negatively impact women and lead to breast cancer (BC). Endocrine disruptors can affect major pathways through various means, including histone modifications, the erroneous expression of microRNA (miRNA), DNA methylation, and epigenetic modifications. However, it is still uncertain if the epigenetic modifications triggered by EDCs can help predict negative outcomes. Consequently, it is important to understand how different endocrine disrupters or signals interact with epigenetic modifications and regulate signalling mechanisms. This study proposes that the epigenome may be negatively impacted by several EDCs, such as cadmium, arsenic, lead, bisphenol A, phthalates, polychlorinated biphenyls and parabens, organochlorine, and dioxins. Further, this study also examines the impact of EDCs on lifestyle variables. In breast cancer research, it is essential to consider the potential impacts of EDC exposure and comprehend how EDCs function in tissues.

Keywords: breast cancer; dietary exposure; endocrine disruptors; epigenetic.

Figure 1

The effects of endocrine-disrupting chemicals (EDCs) and the mechanism(s) by which epigenetic modification, including DNA methylation, expression of aberrant microRNA (miRNA), and histone modification, is one mechanism assumed to be a primary pathway leading to the untoward effects of endocrine disruptors (the figure was designed using BioRender graphics: https://www.biorender.com, accessed on 28 July 2024).

Figure 2

Endocrine disruptors and risk factors mediate epigenome modifications that increase the risk of breast cancer. EDC may prolong puberty and increase mammary epithelial cell proliferation, allowing for a longer duration or faster rate of epigenetic remodelling of the developing mammary gland, resulting in chromatin destabilisation, mispackaging of genes in active/inactive domains, and aberrant expression of genes in key regulatory pathways. Mutations in HMTs (histone methyltransferases), HDMs (histone methyltransferases), and H3.3 (Histone variant H3.3) increase Histone deacetylase 1 (HDAC1) but reduce HATs (histone acetyltransferases) (the figure was designed using BioRender graphics: https://www.biorender.com, accessed on 28 July 2024).

Figure 3

Epigenetic control is crucial in mitigating the toxic effects of cadmium (Cd²⁺), a heavy metal that causes serious health and environmental problems. Cadmium can alter cellular homeostasis and cause cancer, often through non-genetic mechanisms such as DNA methylation, histone changes, and microRNA (miRNA) control. The disrupting effects of cadmium on MAPK pathways on cellular signalling and health. Figure highlights the direct and indirect effects of Cd²⁺ interference on cellular function, which lead to aberrant cell responses and elevated breast cancer. These disruptions can result in altered gene expression and impaired cell proliferation, ultimately contributing to tumourigenesis (the figure was designed using BioRender graphics: https://www.biorender.com, accessed on 8 August 2024).

Figure 4

Growth factor receptors activated by arsenic stimulate the PI3K/AKT pathway, which promotes angiogenesis, cell cycle progression, and cellular proliferation. Through the TRAIL receptor and reactive oxygen species, arsenic triggered apoptosis by upregulating pro-apoptotic markers and down-regulating anti-apoptotic signs. These mechanisms illustrate how arsenic can exert both pro-survival and pro-death signals within cells, leading to complex interplay in tumour standing these pathways is crucial for developing targeted therapies that could mitigate the adverse effects of arsenic exposure while potentially harnessing its apoptotic capabilities against cancer cell biology. Understanding these pathways is crucial for developing targeted therapies that could mitigate the adverse effects of arsenic exposure while potentially harnessing its apoptotic capabilities against cancer cells (the figure was designed using BioRender graphics: https://www.biorender.com, accessed on 9 August 2024).

Figure 5

Lead inhibits delta-aminolevulinic acid dehydratase (ALAD) and enhances the δ-aminolevulinic acid substrate, which is known to increase ROS production and oxidative stress within cells. Epigenetic alterations can modify gene expression without changing the underlying DNA sequence, making them an important role in breast cancer growth and progression (the figure was designed using BioRender graphics: https://www.biorender.com, accessed on 10 August 2024).

Figure 6

Potential pathways underlying BPA-induced breast cancer formation and progression. Bisphenol A (BPA), oestrogen receptor alpha (ERA), G-protein-coupled receptor 30 (GPR30), ten-eleven translocation 2 (TET2), Snail family zinc finger protein (SNAIL), and extracellular signal-regulated kinase 1/2 (ERK1/2). These elements interact in intricate ways to alter biological pathways, eventually leading to cancer linked with BPA exposure. Understanding these pathways is critical for developing tailored treatments and prevention methods for BPA-induced breast cancer (the figure was designed using BioRender graphics: https://www.biorender.com, accessed on 12 August 2024).

Figure 7

All the way through the Plyc, Mekk, IRAK, and PLC-β signalling pathways, phthalates altered the gene expression in breast cancer. These changes in gene expression could potentially influence tumour growth and metastasis, highlighting the need for further research into the mechanisms by which phthalates affect cellular processes. Understanding these pathways may lead to new therapeutic strategies for breast cancer treatment (the figure was designed using BioRender graphics: https://www.biorender.com, accessed on 13 August 2024).

Figure 8

PCB activates relevant upstream signalling cascades, including p38, extracellular regulated protein kinases (ERK), and mitogen-activated protein kinase (MAPK). This includes phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt. Reactive oxygen species (ROS) were produced following a PCB challenge and antioxidant therapy, which significantly reduced the activation of these axis signalling pathways by PCBs and caused breast cancer metastasis and progression. This interaction underscores the potential for targeted therapies that could disrupt these pathways, offering new avenues for treatment in patients affected by PCB-related breast cancer (the figure was designed using BioRender graphics: https://www.biorender.com, accessed on 14 August 2024).

Figure 9

Epigenetic changes can influence the expression of genes involved in paraben metabolism, detoxification, and response. Parabens, including methyl paraben and propylparaben, are weak estrogen mimics that attach to estrogen receptors. Aberrant hypermethylation of CpG islands in promoter regions can mute genes that metabolise or detoxify paraben, including UDP-glucuronosyl transferees (UGTs) and sulfotransferases. Their estrogenic action may impact breast cancer cell proliferation, especially in ER-positive tumours. Parabens may affect the expression of microRNA (miR-155, miR-21), which regulate genes involved in cell cycle control, apoptosis, and estrogen response (the figure was designed using BioRender graphics: https://www.biorender.com, accessed on 16 August 2024).

Figure 10

Epigenetic inactivation of organochlorine-responsive pathways in breast cancer entails suppressing cellular activity and imitating or interfering with estrogen signalling, which is crucial in hormone receptor-positive breast cancers. Aberrant methylation of gene promoters can silence detoxifying enzymes such as CYP1A1 and glutathione S-transferases (GSTs), which metabolise OCs. Epigenetically silencing genes that encode hormone receptors, such as ESR1 for ERα, can influence tumour responsiveness to estrogen (the figure was designed using BioRender graphics: https://www.biorender.com, accessed on 16 August 2024).

Figure 11

The AhR is a ligand-activated transcription factor that regulates gene expression by translocating to the nucleus after binding to dioxins or similar ligands. Aberrant methylation of CpG islands in promoter regions has the potential to silence critical AhR pathway genes such as CYP1A1 and CYP1B1, which are involved in the detoxification of hazardous drugs. Loss of AhR function may disrupt cell proliferation and apoptosis, contributing to carcinogenesis in breast cancer (the figure was designed using BioRender graphics: https://www.biorender.com, accessed on 19 August 2024).