Zhao Yue, Ruan Xiangyan, Wang Husheng, Li Xue, Gu Muqing, Wang Lijuan, Li Yanglu, Seeger Harald, Mueck Alfred O
Department of Gynecological Endocrinology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.
Department of Gynecological Endocrinology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China; Research Centre for Women's Health and University Hospital, University of Tuebingen, Tuebingen, Germany.
Maturitas. 2017 Aug;102:26-33. doi: 10.1016/j.maturitas.2017.05.007. Epub 2017 May 13.
During menopausal hormone therapy (MHT) a possible increase in breast cancer risk is thought to depend mainly on the progestogen component. In vitro studies have shown that the progesterone receptor membrane component 1 (PGRMC1) is important for tumor proliferation induced by progestogens. The primary aim of this study was to compare for the first time the natural progestogen, progesterone (P), with a synthetic progestogen, norethisterone (NET), using a xenograft model.
MCF7 cells, transfected with PGRMC1 plasmid or empty vector, were injected into nude mice and estradiol (E2) pellets were implanted. After 12days, NET or P or placebo pellets were implanted. Tumor volumes in all groups (6 mice/group) were monitored for 6-7 weeks. Immunohistochemical expression of PGRMC1 and KI-67 was assessed. These experiments were repeated using T47D cells.
Compared with the control condition, E2 and sequential E2/NET combination increased xenograft tumor growth with MCF7 and T47D cells that transgenically expressed PGRMC1 (p<0.01); progesterone did not increase growth. Breast cancer cells transfected with empty vectors did not respond to either progestogen. Comparing KI-67 and PGRMC1 expression, the Pearson correlation was r=0.848, p=0.002.
E2 plus NET increases tumor growth in human breast cancer cells overexpressing PGRMC1, but there is no change with progesterone. To our knowledge, this is the first comparison of both progestogens in vivo using nude mice, which are frequently used in xenograft models. Clinical trials are needed to determine whether women with overexpression of PGRMC1 are at increased risk of breast cancer if NET instead of progesterone is used in MHT.
在绝经激素治疗（MHT）期间，乳腺癌风险可能增加被认为主要取决于孕激素成分。体外研究表明，孕激素受体膜成分1（PGRMC1）对孕激素诱导的肿瘤增殖很重要。本研究的主要目的是首次使用异种移植模型比较天然孕激素孕酮（P）与合成孕激素炔诺酮（NET）。
将转染了PGRMC1质粒或空载体的MCF7细胞注射到裸鼠体内，并植入雌二醇（E2）微丸。12天后，植入NET或P或安慰剂微丸。监测所有组（每组6只小鼠）的肿瘤体积6 - 7周。评估PGRMC1和KI-67的免疫组化表达。使用T47D细胞重复这些实验。
与对照条件相比，E2以及序贯E2/NET组合增加了转基因表达PGRMC1的MCF7和T47D细胞的异种移植肿瘤生长（p<0.01）；孕酮未增加生长。转染空载体的乳腺癌细胞对两种孕激素均无反应。比较KI-67和PGRMC1表达，Pearson相关性为r = 0.848，p = 0.002。
E2加NET增加了过表达PGRMC1的人乳腺癌细胞的肿瘤生长，但孕酮无变化。据我们所知，这是首次在体内使用常用于异种移植模型的裸鼠对两种孕激素进行比较。需要进行临床试验以确定在MHT中使用NET而非孕酮时，PGRMC1过表达的女性患乳腺癌的风险是否增加。
