• 2018-07
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  • In our xenograft study Fig Fig we


    In our xenograft study (Fig. 7, Fig. 8), we observed that DYD acts very similarly to progesterone; the initial faster tumor growth in the PGRMC1-transfected MCF7 tumor was not significant compared with that with progesterone, in GF 109203X sale to the greater tumor growth observed with norethisterone. This was the case only in the two PGRMC1 xenografts: in both non-transfected xenografts there were no significant differences between groups. Our present results reproduce those of our earlier xenograft study [22], i.e. the neutral effect of progesterone but significantly greater tumor growth with NET compared with estradiol alone. In our present xenograft study, we used in contrast to our earlier study castrated mice to attain defined E2 levels achieved by the implanted E2 pellets. From the two studies it can be suggested that the source of estradiol, endogenous or exogenous, does not make a difference to breast tumor proliferation. It should be mentioned that for animal studies, the higher steroid dosages are equivalent to their use in humans, and details about the estradiol pellets used in our study are presented elsewhere [28]. The E2 levels achieved in the mice are about 1000 pg/ml, which is about 10-fold higher than their levels in MHT. Likewise, the progestogens used as pellets (progesterone, NET) or via intra-gastric administration (DYD) achieved up to 10-fold higher levels, which are described as equivalent dosages for studies in mice [29]. Investigations into possible mechanisms of PGRMC1 action in the breast were not the aim of the present study. Several investigations indicate different intracellular genomic or non-genomic mechanisms [30]. In addition, there may be cross-talk with stromal growth factors, i.e. interaction with the HER-receptor family [18], and vascular effects have also been described [14]. ERalpha seems to play an important role, as demonstrated with fulvestrant (blocking ERalpha activity), which abolished progestogen-induced proliferative effects in PGRMC1-transfected cells [13]. Norethisterone induces phosphorylation of PGRMC1 at the casein kinase 2-phosphorylation site Ser181 [31]. This enables PGRMC1 to react with prohibitin, a coregulator repressing ERalpha transcriptional activity, with consequent activation of ERalpha, which can upregulate transcription of ERalpha-dependent genes starting proliferation. Recent investigations of gene expression interestingly show that norethisterone can not only increase breast-cell viability, but also increase expression of PGRMC1, which could be suppressed by microRNA-181a, leading to the suggestion of using microRNA-181 to reduce breast cancer risk in MHT [32]. Further research on activation mechanisms of PGRMC1 will provide deeper insights into the mode of action of progestogens. The actions of PGMC1 in the breast may not only be important with regard to progestogen effects. We recently found overexpression of PGRMC1 in the tissue of breast cancer patients but not in their healthy tissue, and that PGRMC1 could predict a worse prognosis in breast cancer patients because its expression is correlated with larger tumor size, worse grading and lymph node status, shorter disease-free interval and poorer survival [12]. The predictive value of PGRMC1 assessed by these clinical parameters may even be greater than that of Ki67 [12]. One limitation might be that we only used T47D and not MCF7 cells in our in-vitro experiments. However, progestogen effects in MCF7 cells have already been extensively tested, and we could even make \"historical\" comparisons with our own earlier in-vitro research [[14], [15], [16], [17], [18], [19]]. We decided to perform in-vitro tests only in T47D cells because published data are rare, and T47D cells have recently been recommended for assessing progestogen effects in breast cancer research [27]. Nevertheless, in-vitro and animal experiments can never replace clinical studies.
    Conflict of interest