In a recent study published in the journal Environmental Health Perspectives, researchers examined published studies investigating the genotoxicity of potentially carcinogenic chemicals and their roles in inducing mammary tumors and activating progesterone or estradiol signaling.
Study: Application of the Key Characteristics Framework to Identify Potential Breast Carcinogens Using Publicly Available in Vivo, in Vitro, and in Silico Data. Image Credit: crystal light/Shutterstock.com
The researchers aimed to identify chemicals that could present breast cancer risk to humans.
Background
Recent statistics indicate that breast cancer is the most prevalent form of cancer and the major cause of cancer-related mortality among women across the world. In the United States (U.S.), the lifetime risk of women developing breast cancer is double that of the risk of developing lung cancer.
Furthermore, the incidence of breast cancer among younger women is increasing, with mortality rates due to breast cancer among women between the ages of 20 and 49 years being double that of other forms of cancers affecting individuals of both sexes.
A nine-year assessment since 2010 also indicates that the diagnostic rate of breast cancer among women below the age of 40 has increased by 1.1% each year.
A potentially effective approach to reducing the risk of breast cancer is identifying potentially carcinogenic or mammary tumor-inducing chemicals that can cause endocrine disruption or genotoxicity and taking informed measures to reduce exposure to such chemicals.
Using animal models, such as rodents that have similar tissue structures, and genotoxicity and humoral pathways involved in mammary tumors as humans, can help identify chemicals that can be potentially carcinogenic to humans.
About the study
In the present study, the researchers used databases such as monographs from the International Agency for Research on Cancer (IARC) and ToxCast from the U.S. Environmental Protection Agency to identify chemicals that have shown the ability to induce mammary tumors, as well as stimulate the synthesis of progesterone or estradiol and activate estrogen receptors, in in vitro experiments.
These chemicals were classified based on key characteristics such as genotoxicity and endocrine activity strength, and these key characteristics were evaluated for their ability to predict the mammary tumor-inducing activity of these chemicals.
A list of key characteristics has been developed by the IARC for known human carcinogens to document their biological effects and provide a framework for identifying other chemicals that could be potentially carcinogenic.
The documented key characteristics include genotoxicity, increase in cell proliferation, cell signaling alterations, inflammation, epigenetic modifications, and immunosuppression. The presence of one or more of these key characteristics indicates potential carcinogenic activity.
While genotoxicity and the ability to alter deoxyribonucleic acid (DNA) or impact DNA repair mechanisms are the two major key characteristics for most carcinogens, hormone receptor activity and endocrine signaling are important key characteristics when considering breast cancer.
The roles of the progesterone and estrogen receptors are important in understanding the risk of and developing treatment options for breast cancer.
The chemicals investigated in this study were classified based on breast cancer-relevant exposures according to their endocrine activity and genotoxicity, and an existing list of mammary carcinogens from 2007 was updated to include chemicals that activate endocrine signaling pathways relevant to breast cancer.
The proportion of mammary carcinogens that exhibit biological effects, such as activating breast-cancer-relevant endocrine pathways, was also calculated as a proportion of all the chemicals screened in the study.
Results
The results reported 279 mammary carcinogens and 642 other chemicals with the key characteristic of stimulating progesterone or estrogen signaling, cumulatively presenting a list of 921 breast cancer-relevant exposures.
Furthermore, other key characteristics such as genotoxicity, agonism of estrogen receptors, and steroidogenicity were also enriched in these mammary carcinogens, indicating that key characteristics were an effective method of predicting whether a chemical is capable of inducing mammary tumors in rodents and, by extension, pose breast cancer risk in humans.
Among the key characteristics observed, steroidogenesis was more common among mammary carcinogens than agonism of estrogen receptors, while most of them increased the secretion of progesterone and estradiol.
The researchers believed that given the identification of numerous additional chemicals exhibiting key characteristics of breast cancer risk, it is important to develop better assessment methods and improved assays for testing mammary-tumor-inducing abilities of chemicals and reducing exposures.
Conclusions
To summarize, this study identified a total of 921 rodent mammary carcinogens or chemicals that may induce mammary tumors. Hence, they may pose breast cancer risk in humans.
The findings highlight the importance of using the key characteristics framework in identifying potential mammary carcinogens.
Journal reference:
- Kay JE, Brody JG, Megan S, et al. (2024). Application of the key characteristics framework to identify potential breast carcinogens using publicly available in vivo, in vitro, and in silico Data. Environmental Health Perspectives, 132(1), 017002. doi: 10.1289/EHP13233. https://ehp.niehs.nih.gov/doi/10.1289/EHP13233
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