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  • br Funding This work was


    Funding This work was supported by the National Natural Science Foundation of China (grant number 81671411); Beijing Natural Science Foundation (grant number 7162062); Beijing Nova Program Interdisciplinary Cooperation Projects (grant number Z161100004916045); Beijing Municipality Health Technology High-level Talent (grant number 2014-2-016); Beijing Municipal Administration of Hospitals ‘Ascent Plan, Code: DFL20181401.
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    Introduction The expression of sex steroid receptors in breast cancer tissue has been recognized as being able to predict the clinical response to endocrine treatments. Knockout of the estrogen receptor (ER) and progesterone receptor (PR) genes prevents complete mammary gland development in mature mice [1], [2]. Thus, the effects of estrogen and progesterone on the mammary gland are believed to be mediated by their ER and PR. However, the exact mechanisms by which estrogen and progestestogens regulate the proliferation and differentiation of human breast hoechst remains less known. It is generally accepted that female sex hormones are linked to the etiopathogenesis of breast cancer. Results from a large randomized clinical trial, the Women\'s Health Initiative, indicate a poorer outlook in users of combined estrogen-progestin therapy, represented by a larger proportion of tumors with lymph-node metastases and by differentiated tumors [3], [4]. By contrast, observational studies have repeatedly reported fewer malignant clinical features and improved prognosis in hormone therapy (HT) users [5], [6]. However, the impact of HT use on breast-cancer prognosis and clinical characteristics is not well understood. Just as the animal experiments and observations in women suggest, the treatment with estrogen/progestogen may have diverging effects on the expression of ER and PR isoforms in the breast epithelium [7].
    Materials and methods
    Discussion This study demonstrates that various progestogens combined with E2 had different effects on breast cell growth. These effects had an inverse correlation with the changes of the PRA/PRB ratio. E2\'s antiapoptotic effects on MCF-7 cells may be related to the expression of ERα phosphorylation. The antiapoptotic effect of E2 alone was counteracted by the combination of progestogens, especially at low concentrations of E2. This confirms the present consensus of HT in that low doses of E2 may be more suitable with respect to lowering breast cancer risk. In addition, our findings suggest that synthetic progestins combined with E2 induced more prominent changes in the expression of ERs and PRs than the progesterone plus E2. Its significance on the effects of breast cells during HT should be considered. In breast cancer cell lines, cell death induced by antiestrogen treatment [8] and inhibition by E2[9] has been reported. Like the present study, pure E2 significantly decreased the expressions of caspase-3. An inhibitory effect of E2 on caspase-3 level was also noted in the report of Somaï et al [10]. In the current study, pure E2 induced antiapoptosis of MCF-7 cells, in which ERα expression was increased, whereas the expressions of ERβ, PRA, and PRB were not altered. This is compatible with several reports in that estrogen may induce anti-apoptotic effects in ERα-positive breast cancers [11], [12] and that the effects may be mediated by ERα. This study has also shown that 1 nM E2 plus MPA and 10 nM E2 plus NET significantly increased caspase-3 expression and entirely abolished E2-induced augmentation of ERα expression. It is compatible with other reports that progestin can inhibit the expression of ER gene transcription [13], [14]. In addition, our results also reveal that PRB expression significantly increased, whereas PRA expression did not change, in the culture with 1 nM E2 plus MPA and 10 nM E2 plus NET. This demonstrates that MPA and NET inhibiting E2-induced transcription may be triggered by PRB. Similar findings were also reported by Chalbos and Galtier [15], in which synthetic progestin R5020 inhibited estradiol-induced pS2 levels in MCF-7 cells whereas PRB, but not PRA, inhibited the gene transcription induced by ER. Although in the present study, significant increase of ERα expression was still noted in E2 plus CPA or P4, the decreased caspase-3 expression by E2 was entirely limited. In contrast to the increased PRB expression in E2 combined with MPA and NET, E2 plus CPA or P4 induced no change of PRB nor decreased PRA and PRB. The present study demonstrates that decreased ERα, mediated by increased PRB expression, may induce apoptosis of breast cancer cells.