Endocrine-disrupting compounds and metabolomic reprogramming in breast cancer

Abstract

Endocrine-disrupting chemicals pose a growing threat to human health through their increasing presence in the environment and their potential interactions with the mammalian endocrine systems. Due to their structural similarity to hormones like estrogen, these chemicals can interfere with endocrine signaling, leading to many deleterious effects. Exposure to estrogenic endocrine-disrupting compounds (EDC) is a suggested risk factor for the development of breast cancer, one of the most frequently diagnosed cancers in women. However, the mechanisms through which EDCs contribute to breast cancer development remain elusive. To rapidly proliferate, cancer cells undertake distinct metabolic programs to utilize existing nutrients in the tumor microenvironment and synthesize macromolecules de novo. EDCs are known to dysregulate cell signaling pathways related to cellular metabolism, which may be an important mechanism through which they exert their cancer-promoting effects. These altered pathways can be studied via metabolomic analysis, a new advancement in -omics technologies that can interrogate molecular pathways that favor cancer development and progression. This review will summarize recent discoveries regarding EDCs and the metabolic reprogramming that they may induce to facilitate the development of breast cancer.

Keywords: bisphenols; breast cancer; endocrine-disrupting compounds; metabolomics; phthalates; zeranol.

Figure 1.. Chemical structures of environmentally relevant estrogenic endocrine disrupting compounds (EDCs).

The structures of estrogen (beta-estradiol), bisphenol-A (BPA), Di(2-ethylhexyl)phthalate (DEHP), alpha-zeranol (aZAL), and polychlorinated biphenyls (PCBs) are shown.

Figure 2.. Environmental sources of endocrine disrupting compounds (EDCs). Humans are exposed to environmental EDCs from various sources.

Historically, polychlorinated biphenyls (PCBs) were added into electrical conductors and fluid coolants. Phthalates are included in polyvinyl chloride (PVC) pipes and soft, malleable plastics, like food bagging. Bisphenols are incorporated into hard, stiff plastics, like water bottles. Zeranols are produced by the Fusarium fungus, a common contaminant of agricultural crops like corn and maize [–150]. Human EDC exposure levels are shown.

Figure 3.. The role of endocrine disrupting compounds (EDCs) throughout breast cancer initiation, progression, and metastasis.

EDCs likely have diverse mechanisms throughout carcinogenesis [–161].

Figure 4.. Major sites of action and molecular effects of endocrine disruptor exposure.

EDCs can work through diverse molecular mechanisms upon arrival at a target site, though some pathways are conserved across various types of compounds. Bisphenols and PCBs both initiate aerobic glycolysis and lipid biosynthesis within the mammary gland. Phthalates and PCBs can both activate AhR in different target tissues. Other pathways, like nucleotide synthesis, are specific to certain compounds.