Effects of estradiol and progestogens on human breast cells: Regulation ofsex steroid receptors

Objectives: To examine the effects of 17β-estradiol (E₂) and progestogens, used in hormone therapy, on estrogen receptors (ER), progesterone receptors (PR), and human breast tumor cell growth. Materials and methods: MCF-7 cells were incubated in pure E₂ (1nM and 10nM) as well as in E₂ in conjunction with 10nM progestogens, including progesterone (P4), medroxyprogesterone acetate (MPA), norethisterone acetate (NET), and cyproterone acetate (CPA). Cell proliferation, apoptosis, expression of caspase-3, and both ER and PR isoforms were evaluated. Results: Caspase-3 was significantly diminished in cultures with only E₂, whereas ERα significantly increased. A significant increase of caspase-3 in addition to the entire abolishment of E₂-induced augmentation of ERα was observed in 1nM E₂ plus MPA and 10nM E₂ plus NET, whereas PR isoform B (PRB) was significantly increased. The ratios of apoptosis: proliferation significantly increased in 1nM E₂ plus progestogens (except P4) and 10nM E₂ plus NET. The changes of the PRA/PRB ratio were inversely related to the changes of the apoptosis to proliferation ratio. Significant increase of ERβ and PRB was noted in the E₂ plus MPA or NET, in addition to a significant increase of ERα and decrease of PRA in the E₂ plus CPA, as well as an increase of ERα and decrease of PRA and PRB in the E₂ plus P4. Conclusions: The combination of E₂ and various progestogens resulted in diverging effects on ERs and PRs expressions, which induced different effects on MCF-7 cell growth. Compared with P4, aberrant hormone and biological activity of synthetic progestin, by way of altered receptor expression, may be an important factor in affecting breast cell growth.