University Women's Hospital, Tuebingen, Germany.
Menopause. 2013 May;20(5):504-10. doi: 10.1097/GME.0b013e3182755c97.
Clinical trials have demonstrated an increased risk of breast cancer during estrogen/norethisterone (NET) therapy. With this in mind, the effects of estrogen/NET combination on the proliferation of breast cancer cells overexpressing the progesterone receptor membrane component 1 (PGRMC1) were examined. The same combination was used for the first time in a mouse xenograft model to determine its effects on tumor development.
MCF-7 cells were stably transfected with PGRMC1 expression plasmid (WT-12 cells) or empty vector control (pcDNA-3HA). NET, medroxyprogesterone acetate (MPA), and progesterone were tested alone and sequentially and continuously combined with estradiol (E2). Six-week-old nude mice were inoculated with E2 pellets 24 hours before the injection of tumor cells into both flanks (n = 5-6 mice per group). After 8 days, animals were inoculated with a NET pellet or with placebo pellets, and tumor volumes were recorded twice a week.
NET alone significantly increased the proliferation of WT-12 cells, MPA was effective only at the two highest concentrations, and progesterone had no effect. The twofold to threefold E2-induced increase (10 M) was not significantly influenced by the addition of the various progestogens. In contrast, 10 M E2 had no effect; however, addition of MPA and NET triggered a significant proliferative response. In vivo, a sequential combination of NET and E2 also significantly increased the tumor growth of WT-12 cells; empty vector cells did not respond to NET.
We have demonstrated for the first time that an E2/NET combination increases the proliferation of PGRMC1-overexpressing breast cancer cells, both in vivo and in vitro. Our results suggest that undetected tumor cells overexpressing PGRMC1 may be more likely to develop into frank tumor cells in women undergoing E2/NET hormone therapy.
临床试验表明，雌二醇/去甲孕酮（NET）治疗会增加乳腺癌风险。考虑到这一点，本研究检测了雌二醇/NET 联合用药对孕激素受体膜组份 1（PGRMC1）过表达的乳腺癌细胞增殖的影响。首次将该联合用药应用于小鼠异种移植模型，以确定其对肿瘤发展的影响。
MCF-7 细胞通过 PGRMC1 表达质粒（WT-12 细胞）或空载体对照（pcDNA-3HA）稳定转染。单独和连续联合使用 NET、醋酸甲地孕酮（MPA）和孕酮，并与雌二醇（E2）联合用药。6 周龄裸鼠在肿瘤细胞注射到两侧前 24 小时植入 E2 微球（每组 5-6 只小鼠）。8 天后，动物植入 NET 微球或安慰剂微球，并每周两次记录肿瘤体积。
NET 单独使用可显著增加 WT-12 细胞的增殖，MPA 仅在两个最高浓度有效，孕酮无效。两倍至三倍的 E2 诱导增加（10 M）不受各种孕激素的影响。相比之下，10 M E2 没有影响；然而，添加 MPA 和 NET 会引发明显的增殖反应。在体内，NET 和 E2 的序贯联合也显著增加了 WT-12 细胞的肿瘤生长；空载体细胞对 NET 无反应。
我们首次证明，E2/NET 联合用药可增加 PGRMC1 过表达的乳腺癌细胞的增殖，无论是在体内还是体外。我们的研究结果表明，在接受 E2/NET 激素治疗的女性中，未检测到的过表达 PGRMC1 的肿瘤细胞更有可能发展为明显的肿瘤细胞。
