Role of Estrogens in the Development of Breast Cancer

The mechanism by which Es increase risk of overt BC is still the subject of debate (Figure 4). Es can stimulate the proliferation of breast epithelial cells, leading to genetic mistakes and a transformed cellular phenotype (72). Additionally, Es can accelerate the growth of occult cancers resulting in increased incidence of overt disease (73). These promotional properties of Es appear to be largely mediated through ER signaling system. Consequently, both SERMs and aromatase inhibitors should attenuate such promotion.

Figure 4. Mechanisms whereby E may cause breast cancer: (1) via the ER, (2) via metabolism of E. Note that anti-estrogens block only ER-mediated events, whereas aromatase inhibitors block both ER and metabolic pathways

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However, evidence is accumulating that E metabolites are genotoxic (74). In particular, metabolism of Es via catechols (2-/4-hydroxyestradiol or hydroxyestrone) may produce reactive quinones which can directly interact with and mutate DNA, initiating carcinogenesis (75-77). Furthermore, these reactions also generate reactive oxygen metabolites that may also damage DNA. The enzymes in this metabolic pathway may be raised in women at risk of BC (72, 75, 76, 78). These genotoxic processes appear independent of ER signaling. SERMs are therefore unlikely to reduce genotoxic damage (Figure 4): in contrast aromatase inhibitors which reduce E levels would. Indeed, it has been shown that BC cells metabolize androgens into E-guanine adducts, and the aromatase inhibitor, letrozole, is capable of inhibiting their formation (78).

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