Lack of interactions of SERMs with Asp351 and Phe404 of the oestrogen receptor alpha correlates with endometrial cancer development in patients

Adjuvant hormone therapy of breast cancer using Selective Oestrogen Receptor Modulator (SERM) tamoxifen is the standard of care for premenopausal patients. Besides the reduction in recurrence risk, including contralateral breast cancer incidence, SERMs can exert opposite agonistic effects on bone and cholesterol levels, which can be beneficial for women in the prevention of osteoporosis and coronary heart disease. However, breast cancer, as well as osteoporosis and coronary heart disease, all have much higher incidence in postmenopausal women. Postmenopausal breast cancer patients receive adjuvant therapy with aromatase inhibitors instead of tamoxifen, because of the risk of uterine cancer due to the agonistic side effect on the endometrial cells. Therapy with aromatase inhibitors can induce secondary osteoporosis, which is the opposite of what a SERM would do, if it were safe to use in postmenopausal women. In this article, we show how the results of molecular dynamics simulations that correlate with the clinical development of ER-dependent uterine cancer for well-known SERMs, in particular, reduced of protein–ligand interaction with Asp351 and Phe404 within the ligand-binding domain (LBD) of the ER.