Bisphenols and Risk of Breast Cancer: A Narrative Review of the Impact of Diet and Bioactive Food Components

Abstract

Data from preclinical studies suggest a link between increased risk of breast cancer and exposure to bisphenols at doses below what the United States Food and Drug Administration (FDA) considers as safe for consumption. Bisphenols exert estrogenic effects and are found in canned and plastic wrapped foods, food packaging, and plasticware. Mechanistically, bisphenols bind to the estrogen receptor (ER) and activate the expression of genes associated with cell proliferation and breast cancer. In this paper, we present a narrative literature review addressing bisphenol A and chemical analogs including bisphenol AF, bisphenol F, and bisphenol S selected as prototype xenoestrogens; then, we discuss biological mechanisms of action of these bisphenols in breast cells and potential impact of exposure at different stages of development (i.e., perinatal, peripubertal, and adult). Finally, we summarize studies detailing interactions, both preventative and promoting, of bisphenols with food components on breast cancer risk. We conclude the review with a discussion of current controversies in interpretation of the above research and future areas for investigation, including the impact of bisphenols and food components on breast tumor risk.

Keywords: bisphenol; breast cancer; epigenetics; estrogen receptor (ER); nutrition.

Figure 1

(A) Chemical structure of bisphenol analogs. Chemical structures are from PubChem. (B) Terms used for PubMed search.

Figure 2

Summary of BPA mechanisms of action via estrogen receptors. BPA activates both genomic and non-genomic estrogen signaling pathways. Genomic signaling involves activation of the nuclear ER proteins ERα and ERβ. Nuclear ER bind as either homo- or heterodimers to induce transcription of genes controlled by estrogen responsive elements (ERE). Non-genomic actions of BPA involve signaling through G protein coupled estrogen receptor (GPER) molecules, which activate signal transduction pathways (e.g., ERK1/2) via kinase activity. BPA binding to GPER activates downstream signaling by epidermal growth factor receptor (EGFR) and focal adhesion kinase (FAK). GPER signaling through ERK1/2 stimulates transcription of c-FOS-dependent genes. Under hypoxic conditions, BPA activation of GPER promotes HIF1α-dependent induction of VEGF, which is associated with increased proliferation, migration, and angiogenesis.