Risk of breast cancer during hormone replacement therapy: mechanisms

Regarding estrogen replacement therapy, two main mechanisms have to be considered for it to be discussed as a potential carcinogen in the breast, and also considering the World Health Organization definition of estrogens and estrogen/progestogen combinations as "carcinogenic": (i) the proliferative/apoptotic effects on already pre-existing estrogen-sensitive cancer cells and (ii) the production of possible genotoxic estrogen metabolites. By addition of the progestogen component, as is usual in non-hysterectomized women, both mechanisms can lead to an increased risk compared to estrogenonly therapy. The detailed mechanisms underlying the development of the benign breast epithelial cell into clinically relevant breast cancer cells are very complicated. Based on these mechanisms, the following simplified summary of the main steps explains that: (i) an increased risk cannot be excluded, (ii) especially when estrogens are combined with progestogens, but (iii) there are differences between the preparations used in therapy; (iv) the risk seems to be very rare, needing very special cellular and extracellular conditions, (v) and could even be decreased in special situations of estrogen therapy. It is concluded that when critically reviewed, an increased risk of breast cancer during hormone replacement therapy cannot be excluded in very rare cases. Definitive mechanistic evidence for a possible causal relationship with carcinogenesis still remains open.