Preclinical breast effects of a tissue selective estrogen complex (TSEC) including conjugated estrogen with bazedoxifene.

The first tissue-selective estrogen complex (TSEC), consisting of a combination of a conjugated equine estrogen (CEE) and bazedoxifene (BZA), has been approved for treatment of the menopause in the USA and European Union. We have postulated that this TSEC might block the estrogenic effects of CEE on breast tissue and thereby prevent breast cancer growth. This manuscript, representing a presentation at a Festschrift honoring Evan Simpson, reviews our published data BZA blocked the in vitro effects of both estradiol and CEE on cell growth and gene expression in MCF-7 cells. BZA completely blocked CEE- or E2-stimulated ductal and terminal end bud growth of immature murine mammary glands and the growth of experimental breast cancers. These findings provide a rationale for future clinical studies to determine whether this TSEC prevents the growth of occult breast cancer in women.

Differential utilization of nuclear and extranuclear receptor signaling pathways in the actions of estrogens, SERMs, and a tissue-selective estrogen complex (TSEC).

Estrogens act through nuclear and extranuclear initiated pathways involving estrogen receptors (ERs) to regulate gene expression and activate protein kinases. We investigated the involvement of extracellular signal-regulated kinase2 (ERK2) and ERα in the activities of estradiol (E2), conjugated estrogens (CEs), selective estrogen receptor modulators (SERMs), and a Tissue-Selective Estrogen Complex (TSEC), a combination of a SERM and CE that has a blended activity. We found that CE and individual CE components were generally less effective than E2 in ERK2 recruitment to chromatin binding sites of E2-regulated genes. Likewise, CE was much less agonistic than E2 in stimulation of proliferation of ERα-positive breast cancer cells. The SERM bazedoxifene (BZA) fully suppressed proliferation stimulated by E2 or CE and reversed gene stimulation by CE or E2, as did the antiestrogen Faslodex. Thus, the balance of biological activities mediated through nuclear ERα vs. ERK2-mediated activities is different for CE vs. E2, with CE showing lower stimulation of kinase activity. Furthermore, at the BZA to CE concentrations in TSEC, BZA antagonized CE stimulation of gene expression and proliferation programs in ERα-positive breast cancer cells. The studies provide molecular underpinnings of the different ways in which SERMs and estrogens support or antagonize one another in regulating the chromatin binding of ERα and ERK2, and modulating gene and cell activities. They illuminate how the combined actions of two classes of ER ligands (SERM and CE, present in TSEC) can achieve unique modes of regulation and efficacy.

Tissue-selective estrogen complexes with bazedoxifene prevent metabolic dysfunction in female mice.

Pairing the selective estrogen receptor modulator bazedoxifene (BZA) with estrogen as a tissue-selective estrogen complex (TSEC) is a novel menopausal therapy. We investigated estrogen, BZA and TSEC effects in preventing diabetisity in ovariectomized mice during high-fat feeding. Estrogen, BZA or TSEC prevented fat accumulation in adipose tissue, liver and skeletal muscle, and improved insulin resistance and glucose intolerance without stimulating uterine growth. Estrogen, BZA and TSEC improved energy homeostasis by increasing lipid oxidation and energy expenditure, and promoted insulin action by enhancing insulin-stimulated glucose disposal and suppressing hepatic glucose production. While estrogen improved metabolic homeostasis, at least partially, by increasing hepatic production of FGF21, BZA increased hepatic expression of Sirtuin1, PPARα and AMPK activity. The metabolic benefits of BZA were lost in estrogen receptor-α deficient mice. Thus, BZA alone or in TSEC produces metabolic signals of fasting and caloric restriction and improves energy and glucose homeostasis in female mice.