Genomic-Epidemiologic Evidence That Estrogens Promote Breast Cancer Development

Background: Estrogens are a prime risk factor for breast cancer, yet their causal relation to tumor formation remains uncertain. A recent study of 560 breast cancers identified 82 genes with 916 point mutations as drivers in the genesis of this malignancy. Because estrogens play a major role in breast cancer development and are also known to regulate the expression of numerous genes, we hypothesize that the 82 driver genes are likely to be influenced by estrogens, such as 17 beta-estradiol (E2), and the estrogen receptor ESR1 (ER alpha). Because different types of tumors are characterized by unique sets of cancer driver genes, we also argue that the fraction of driver genes regulated by E2-ESR1 is lower in malignancies not associated with estrogens, e.g., acute myeloid leukemia (AML). Methods: We performed a literature search of each driver gene to determine its E2-ESR1 regulation. Results: Fifty-three of the 82 driver genes (64.6%) identified in breast cancers showed evidence of E2-ESR1 regulation. In contrast, only 19 of 54 mutated driver genes (35.2%) identified in AML were linked to E2-ESR1. Among the 916 driver mutations found in breast cancers, 813 (88.8%) were linked to E2-ESR1 compared with 2,046 of 3,833 in AML (53.4%). Conclusions: Risk assessment revealed that mutations in estrogen-regulated genes are much more likely to be associated with elevated breast cancer risk, while mutations in unregulated genes are more likely to be associated with AML. Impact: These results increase the plausibility that estrogens promote breast cancer development. (C) 2018 AACR.