Background

Exposure to chemicals that cause rodent mammary gland tumors is common, but few studies have evaluated potential breast cancer risks of these chemicals in humans.

Objective

The goal of this review was to identify and bring together the needed tools to facilitate the measurement of biomarkers of exposure to potential breast carcinogens in breast cancer studies and biomonitoring.

Methods

We conducted a structured literature search to identify measurement methods for exposure biomarkers for 102 chemicals that cause rodent mammary tumors. To evaluate concordance, we compared human and animal evidence for agents identified as plausibly linked to breast cancer in major reviews. To facilitate future application of exposure biomarkers, we compiled information about relevant cohort studies.

Results

Exposure biomarkers have been developed for nearly three-quarters of these rodent mammary carcinogens. Analytical methods have been published for 73 of the chemicals. Some of the remaining chemicals could be measured using modified versions of existing methods for related chemicals. In humans, biomarkers of exposure have been measured for 62 chemicals, and for 45 in a nonoccupationally exposed population. The Centers for Disease Control and Prevention has measured 23 in the U.S. population. Seventy-five of the rodent mammary carcinogens fall into 17 groups, based on exposure potential, carcinogenicity, and structural similarity. Carcinogenicity in humans and rodents is generally consistent, although comparisons are limited because few agents have been studied in humans. We identified 44 cohort studies, with a total of > 3.5 million women enrolled, that have recorded breast cancer incidence and stored biological samples.

Conclusions

Exposure measurement methods and cohort study resources are available to expand biomonitoring and epidemiology related to breast cancer etiology and prevention.

Objectives

Perturbations in mammary gland (MG) development may increase risk for later adverse effects, including lactation impairment, gynecomastia (in males), and breast cancer. Animal studies indicate that exposure to hormonally active agents leads to this type of developmental effect and related later life susceptibilities. In this review we describe current science, public health issues, and research recommendations for evaluating MG development.

Data sources

The Mammary Gland Evaluation and Risk Assessment Workshop was convened in Oakland, California, USA, 16-17 November 2009, to integrate the expertise and perspectives of scientists, risk assessors, and public health advocates. Interviews were conducted with 18 experts, and seven laboratories conducted an MG slide evaluation exercise. Workshop participants discussed effects of gestational and early life exposures to hormonally active agents on MG development, the relationship of these developmental effects to lactation and cancer, the relative sensitivity of MG and other developmental end points, the relevance of animal models to humans, and methods for evaluating MG effects.

Synthesis

Normal MG development and MG carcinogenesis demonstrate temporal, morphological, and mechanistic similarities among test animal species and humans. Diverse chemicals, including many not considered primarily estrogenic, alter MG development in rodents. Inconsistent reporting methods hinder comparison across studies, and relationships between altered development and effects on lactation or carcinogenesis are still being defined. In some studies, altered MG development is the most sensitive endocrine end point.

Conclusions

Early life environmental exposures can alter MG development, disrupt lactation, and increase susceptibility to breast cancer. Assessment of MG development should be incorporated in chemical test guidelines and risk assessment.

Targeted gene lists have been used in clinical settings to specify breast tumor type, and to predict breast cancer prognosis and response to treatment. Separately, panels have been curated to predict systemic toxicity and xenoestrogen activity as a part of chemical screening strategies. However, currently available panels do not specifically target biological processes relevant to breast development and carcinogenesis. We have developed a gene panel called the Breast Carcinogen Screen (BCScreen) as a tool to identify potential breast carcinogens and characterize mechanisms of toxicity. First, we used four seminal reviews to identify 14 key characteristics of breast carcinogenesis, such as apoptosis, immunomodulation, and genotoxicity. Then, using a hybrid data and knowledge-driven framework, we systematically combined information from whole transcriptome data from genomic databases, biomedical literature, the CTD chemical-gene interaction database, and primary literature review to generate a panel of 500 genes relevant to breast carcinogenesis. We used normalized pointwise mutual information (NPMI) to rank genes that frequently co-occurred with key characteristics in biomedical literature. We found that many genes identified for BCScreen were not included in prognostic breast cancer or systemic toxicity panels. For example, more than half of BCScreen genes were not included in the Tox21 S1500+ general toxicity gene list. Of the 230 that did overlap between the two panels, representation varied across characteristics of carcinogenesis ranging from 21% for genes associated with epigenetics to 82% for genes associated with xenobiotic metabolism. Enrichment analysis of BCScreen identified pathways and processes including response to steroid hormones, cancer, cell cycle, apoptosis, DNA damage and breast cancer. The biologically-based systematic approach to gene prioritization demonstrated here provides a flexible framework for creating disease-focused gene panels to support discovery related to etiology. With validation, BCScreen may also be useful for toxicological screening relevant to breast carcinogenesis.