孕激素受体膜组分1促进雌孕激素诱导的乳腺癌细胞增生的研究——雌二醇与周期序贯及连续联合比较

doi:10.3969/j.issn.1006-7795.2019.02.016

首都医科大学学报 ›› 2019, Vol. 40 ›› Issue (2): 237-243.doi: 10.3969/j.issn.1006-7795.2019.02.016

孕激素受体膜组分1促进雌孕激素诱导的乳腺癌细胞增生的研究——雌二醇与周期序贯及连续联合比较

李雪¹, 阮祥燕^1,2, 谷牧青¹, 蔡桂举¹, 赵越¹, Alfred O. Meuck^1,2

1. 首都医科大学附属北京妇产医院内分泌科, 北京 100026;
2. 德国图宾根大学妇产医院妇女健康部与妇女健康研究中心, 图宾根 D-72076, 德国

收稿日期:2019-01-04 出版日期:2019-03-21 发布日期:2019-04-15
通讯作者: 阮祥燕 E-mail:ruanxiangyan@163.com
基金资助:
国家自然科学基金（81671411），北京市自然科学基金（7162062），北京市科技新星交叉项目（Z161100004916045），北京市卫生系统高层次卫生技术人才（学科带头人）（2014-2-016），北京市医院管理局登峰计划（DFL20181401），首批北京市级妇幼保健专科示范单位"更年期保健专科"（2018.01-2020.12）。

Progesterone receptor membrane component 1 increases hormone induced proliferation of breast cancer cells——E2 vs sequential combination vs continuous combination

Li Xue¹, Ruan Xiangyan^1,2, Gu Muqing¹, Cai Guiju¹, Zhao Yue¹, Alfred O. Meuck^1,2

1. Department of Endocrinology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, China;
2. Department for Women's Health, University Women's Hospital and Research Center for Women's Health, University of Tuebingen, Tuebingen D-72076, Germany

Received:2019-01-04 Online:2019-03-21 Published:2019-04-15
Supported by:
This study was supported by National Natural Science Foundation of China (81671411), Natural Science Foundation of Beijing (7162062), Beijing Nova Program Interdisciplinary Cooperation Projects (Z161100004916045), Beijing Municipality Health Technology Highlevel Talent (2014-2-016), Beijing Municipal Administration of Hospitals' Ascent Plan(DFL20181401),The First Batch of Beijing Maternal and Child Health Specialist Demonstration units "Menopausal Health Specialist"(2018.01-2020.12).

摘要/Abstract

摘要： 目的研究孕激素受体膜组分1（progesterone receptor membrane component 1，PGRMC1）对激素诱导的乳腺癌细胞的促增生作用，采用单用雌二醇（estradiol，E2）/周期序贯（sequential combination）/连续联合（continuous combination）不同的治疗方案，观察其对乳腺癌细胞增生的影响。方法采用脂质体转染法将T47D稳定转染后，对转染空质粒（T47D-HA-vector）或转染PGRMC1（T47D-HA-PGRMC1）的T47D乳腺癌细胞系，分别用E2（0.1、0.01、0.001 nmol/L），或周期序贯/连续联合方案刺激6 d后，采用CCK-2法检测乳腺癌细胞的增生。结果单用E2（0.1、0.01、0.001 nmol/L），T47D-HA-vector细胞未出现明显增生（P>0.05），T47D-HA-PGRMC1在E2浓度为0.1 nmol/L时与对照组（56%，P<0.05）及与T47D-HA-vector（36%，P<0.05）比均出现明显增加的细胞增生；周期序贯方案，T47D-HA-PGRMC1在E2/炔诺酮（norethisterone，NET）（E2=0.001 nmol/L）刺激时与对照组（82%，P<0.05）及与T47D-HA-vector（63%，P<0.05）比均显著地促进细胞增生。T47D-HA-vector在E2/NET（E2=0.1 nmol/L）刺激时与对照组相比显著地促进细胞增生（37%，P<0.05），T47D-HA-PGRMC1在E2/屈螺酮（drospirenone，DRSP）或E2/NET（E2=0.1 nmol/L）刺激时与对照组（105%，170%，P<0.05）及与T47D-HA-vector（84%，133%，P<0.05）比均显著地促进细胞增生；采用连续联合方案时，T47D-HA-PGRMC1在E2/DRSP或E2/NET（E2=0.001 nmol/L）刺激时与对照组（77%，158%，P<0.05）及与T47D-HA-vector（60%，136%，P<0.05）比均显著地促进细胞增生。T47D-HA-vector在E2/NET（E2=0.1 nmol/L）刺激时与对照组相比显著地促进细胞增生（44%，P<0.05），T47D-HA-PGRMC1在E2/DRSP或E2/NET（E2=0.1 nmol/L）刺激时与对照组（129%，174%，P<0.05）及与T47D-HA-vector（97%，131%，P<0.05）比均显著地促进细胞增生。结论 PGRMC1能够明显促进周期序贯/连续联合方案诱导的乳腺癌增生，与周期序贯方案相比，连续联合方案对T47D增生的促进作用更加明显。

关键词: 研究孕激素受体膜组分1, 周期序贯方案, 连续联合方案, 乳腺癌, 细胞增生

Abstract: Objective To investigate the effect of progesterone receptor membrane component 1 (PGRMC1) on the risk of hormone induced breast cancer, and compare the effects of different treatment regimens:estradiol (E2)/sequential combination/continuous combination(E2/DRSP、E2/NET) on breast cancer proliferation. Methods After stabilized transfection by lipofection, T47D cells transfected with vector(T47D-HA-vector) or PGRMC1(T47D-HA-PGRMC1) were stimulated with E2 alone (0.1, 0.01, 0.001 nmol/L), or sequential/continuous combination. CCK-2 method was performed to measure cell proliferation. Results When treated with E2 (0.001, 0.01, 0.1 nmol/L) alone, T47D-HA-vector cells did not show significant proliferation (P>0.05). At concentration of 0.1 nmol/L, T47D-HA-PGRMC1 cell reached a significant increase in cell proliferation compared with the control group (56%, P<0.05) and compared with T47D-HA-vector group (36%, P<0.05); when treated with sequential combination, T47D-HA-PGRMC1 cell under E2/NET treatment (E2=0.001 nmol/L) showed a significant increase in cell proliferation compared with the control group (82%, P<0.05) and T47D-HA-vector group (63%, P<0.05). Under the same stimulation, when the concentration of E2 reached 0.1 nmol/L, T47D-HA-vector showed a significant increase compared with the control group (37%, P<0.05), and for the T47D-HA-PGRMC1 cell line, when under E2/drospirenone (DRSP) or E2/norethisterone (NET) stimulation (E2=0.1 nmol/L), a significant increase compared with the control group (105%, 170%, P<0.05) and T47D-HA-vector group (84%, 133%, P<0.05) was observed; when treated with the continuous combination, the T47D-HA-PGRMC1 cell line showed a significant increase in cell proliferation under E2/DRSP or E2/NET stimulation (E2=0.001 nmol/L) compared with the control group (77%, 158%, P<0.05) and T47D-HA-vector group(60%, 136%, P<0.05). The T47D-HA-vector cell line showed a significant increase under E2/NET stimulation (E2=0.1 nmol/L) compared with the control group (44%, P<0.05), and the T47D-HA-PGRMC1 cell line under E2/DRSP or E2/NET stimulation (E2=0.1 nmol/L) showed a significant increase in cell proliferation compared with the control group (129%, 174%, P<0.05) and T47D-HA-vector group (97%, 131%, P<0.05). Conclusion PGRMC1 can significantly promote the proliferation of breast cancer cells induced by sequential/continuous combination. Compared with the sequential combination, the continuous combination promoted a higher proliferation of T47D.

Key words: progesterone receptor membrane component 1, sequential combination, continuous combination, breast cancer, cell proliferation

中图分类号:

R711

李雪, 阮祥燕, 谷牧青, 蔡桂举, 赵越, Alfred O. Meuck. 孕激素受体膜组分1促进雌孕激素诱导的乳腺癌细胞增生的研究——雌二醇与周期序贯及连续联合比较[J]. 首都医科大学学报, 2019, 40(2): 237-243.

Li Xue, Ruan Xiangyan, Gu Muqing, Cai Guiju, Zhao Yue, Alfred O. Meuck. Progesterone receptor membrane component 1 increases hormone induced proliferation of breast cancer cells——E2 vs sequential combination vs continuous combination[J]. Journal of Capital Medical University, 2019, 40(2): 237-243.

参考文献

[1] Zhou M G, Li Y C, Wang H D, et al.Analysis on life expectancy and healthy life expectancy in China,1990-2015[J].Zhonghua Liu Xing Bing Xue Za Zhi, 2016, 37(11):1439-1443.
[2] 聂广宁, 王小云, 杨洪艳,等.中国城市女性绝经年龄影响因素调查[J].中国妇幼保健, 2011, 26(8):1191-1193.
[3] Faubion S S, Kuhle C L, Shuster L T, et al.Long-term health consequences of premature or early menopause and considerations for management[J].Climacteric, 2015, 18(4):483-491.
[4] Mitchell E S, Woods N F. Hot flush severity during the menopausal transition and early postmenopause:beyond hormones[J].Climacteric, 2015, 18(4):536-544.
[5] Chen F P, Chang C J, Chao A S, et al. Efficacy of Femarelle for the treatment of climacteric syndrome in postmenopausal women:an open label trial[J].Taiwan J Obstet Gynecol, 2016, 55(3):336-340.
[6] Greenblum C A, Rowe M A, Neff D F, et al. Midlife women:symptoms associated with menopausal transition and early postmenopause and quality of life[J].Menopause, 2013, 20(1):22-27.
[7] 谢梅青, 陈蓉, 任慕兰.中国绝经管理与绝经激素治疗指南[J].协和医学杂志, 2018, 9(6):512-525.
[8] Ahmed I S, Chamberlain C, Craven R J. S2R(Pgrmc1):the cytochrome-related sigma-2 receptor that regulates lipid and drug metabolism and hormone signaling[J].Expert Opin Drug Metab Toxicol, 2012, 8(3):361-370.
[9] Losel R M, Besong D, Peluso J J, et al.Progesterone receptor membrane component 1——many tasks for a versatile protein[J].Steroids, 2008, 73(9-10):929-934.
[10] Rohe H J, Ahmed I S, Twist K E, et al.PGRMC1(progesterone receptor membrane component 1):a targetable protein with multiple functions in steroid signaling,P450 activation and drug binding[J].Pharmacol Ther, 2009, 121(1):14-19.
[11] Kimura I, Nakayama Y, Konishi M, et al. Functions of MAPR (membrane-associated progesterone receptor) family members as hemesteroid-binding proteins[J].Curr Protein Pept Sci, 2012, 13(7):687-696.
[12] Ruan X, Zhang Y, Mueck A O, et al. Increased of progesterone receptor membrane component 1 is associated with aggressive phenotype and poor prognosis in ER-positive and negative breast cancer[J].Menopause, 2017, 24(2):203-209.
[13] Zhang Y, Ruan X, Willibald M, et al.May progesterone receptor membrane component 1(PGRMC1) predict the risk of breast cancer?[J].Gynecol Endocrinol, 2016, 32(1):58-60.
[14] Mueck A O, Ruan X. Benefits and risks during HRT:main safety issue breast cancer[J].Horm Mol Biol Clin Investig, 2011, 5(2):105-116.
[15] Ruan X, Seeger H, Mueck A O. Breast cancer risk during hormone therapy:experimentalversus clinical data[J]. Minerva Endocrinol, 2012, 37(3):59-74.
[16] Yu S, Kim T, Yoo K H, et al. The T47D cell line is an ideal experimental model to elucidate the progesterone-specific effects of a luminal A subtype of breast cancer[J]. Biochem Biophys Res Commun, 2017,486(3):752-758.
[17] Peluso J J, Pappalardo A, Losel R, et al.Progesterone membrane receptor component 1 in the immature rat ovary and its role in mediating progesterone's antiapoptotic action[J].Endocrinology, 2006, 147(6):3133-3140.
[18] Peluso J J, Romak J, Liu X. Progesterone receptor membrane component-1(PGRMC1) is the mediator of progesterone's antiapoptotic action in spontaneously immortalized granulosa cells as revealed by PGRMC1 small interfering ribonucleic acid treatment and functional analysis of PGRMC1 mutations[J].Endocrinology, 2008, 149(2):534-543.
[19] Lodde V, Peluso J J. A novel role for progesterone and progesterone receptor membrane component 1 in regulating spindle microtubule stability during rat and human ovarian cell mitosis[J].Biol Reprod, 2011, 84(4):715-722.
[20] Ahmed I S, Rohe H J, Twist K E, et al.Progesterone receptor membrane component 1(Pgrmc1):a heme-1 domain protein that promotes tumorigenesis and is inhibited by a small molecule[J].J Pharmacol Exp Ther, 2010, 333(2):564-573.
[21] Zhao Y, Ruan X, Wang H, et al. The presence of a membrane-bound progesterone receptor induces growth of breast cancer with norethisterone but not with progesterone:A xenograft model[J].Maturitas, 2017, 102:26-33.
[22] Prifti S, Mall P, Strowitzki T, et al. Synthetic estrogens-mediated activation of JNK intracellular signaling molecule[J].Gynecol Endocrinol, 2001, 15(2):135-141.
[23] 刘芮菡, 孔欣,白慧丽,等.乳腺癌组织与细胞株雄激素受体生物学作用分子机制探讨[J].中华肿瘤防治杂志,2018,25(16):1163-1168.
[24] Mueck A O, Seeger H, Wallwiener D. Comparison of the proliferative effects of estradiol and conjugated equine estrogens on human breast cancer cells and impact of continuous combined progestogen addition[J].Climacteric, 2003, 6(3):221-227.

孕激素受体膜组分1促进雌孕激素诱导的乳腺癌细胞增生的研究——雌二醇与周期序贯及连续联合比较

Progesterone receptor membrane component 1 increases hormone induced proliferation of breast cancer cells——E2 vs sequential combination vs continuous combination

PDF

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

编辑推荐

Metrics

本文评价

[1]	赵越, 阮祥燕, 程姣姣, 谷牧青, 许新, 王月姣. 乳腺癌中PGRMC1表达与临床病理参数的相关性[J]. 首都医科大学学报, 2022, 43(3): 350-356.
[2]	魏常胜, 骆成玉, 张树琦. 环乳晕切口联合乳腔镜腋窝淋巴结清扫在早期乳腺癌保乳手术中的应用[J]. 首都医科大学学报, 2021, 42(6): 1014-1020.
[3]	中华预防医学会妇女保健分会; 中国人体健康科技促进会妇科内分泌与生育力促进专委会. 乳腺癌患者选择性雌激素受体调节剂治疗相关子宫内膜安全管理的中国专家共识(2021版)[J]. 首都医科大学学报, 2021, 42(4): 672-677.
[4]	阮祥燕, 杨瑜, 卢丹, 杜娟, 程姣姣, 谷牧青, 李扬璐, 金凤羽, 段微, 代荫梅, 鞠蕊, 许新, MatthiasKorell, AlfredO.Mueck. 中国首例乳腺癌患者冻存卵巢组织移植成功报道及文献复习[J]. 首都医科大学学报, 2021, 42(2): 177-182.
[5]	邓梦琪, 张艳芹, 常翔宇, 吴迪, 徐春玉, 苗劲蔚. B7-H3基因敲降ES-2细胞系构建及其对细胞增生的影响[J]. 首都医科大学学报, 2021, 42(1): 66-70.
[6]	杨阳, 康骅, 赵菁, 凌煜玮, 赵烨, 王亚军, 戎冬冬. 术前乳腺MRI对乳腺癌保乳手术切缘评估的回顾性分析[J]. 首都医科大学学报, 2020, 41(6): 943-953.
[7]	王爱婷, 鄢丹, 齐宪荣. 包载多西他赛的聚合物胶束抑制小鼠乳腺癌转移作用研究[J]. 首都医科大学学报, 2020, 41(2): 225-230.
[8]	王维, 张紫寒, 翟妍, 桑翠琴, 王淑珍. 子宫体、乳腺双原发癌的临床病理特征[J]. 首都医科大学学报, 2019, 40(6): 857-862.
[9]	张蕴显, 王雅梅, 周萍. 乳腺癌中基于开放染色质的环状RNA互作网络构建及功能分析[J]. 首都医科大学学报, 2019, 40(6): 901-910.
[10]	白向东, 郝雅婷, 张欣雪, 贺强. 脾多肽注射液联合术后化疗对三阴性乳腺癌患者临床疗效的研究[J]. 首都医科大学学报, 2019, 40(6): 911-915.
[11]	张凌燕, 阮祥燕, 蔡桂举, 谷牧青, Alfred O. Mueck. 他莫昔芬治疗转染孕激素受体膜组分1乳腺癌裸鼠模型对乳腺肿瘤组织Ki-67表达的影响[J]. 首都医科大学学报, 2019, 40(4): 533-538.
[12]	王月姣, 阮祥燕, 谷牧青, 蔡桂举, 李雪, 张凌燕, Alfred O. Mueck. 他莫昔芬治疗乳腺癌异种移植瘤裸鼠子宫病理改变[J]. 首都医科大学学报, 2019, 40(4): 539-543.
[13]	闵力, 李恒存, 郭庆东, 王星宇, 张澍田. 新抑癌基因GPD1在结肠癌细胞HCT-8中的作用及其预后潜力研究[J]. 首都医科大学学报, 2019, 40(4): 646-651.
[14]	白向东, 郝雅婷, 张欣雪, 贺强. 雌激素受体阳性和阴性乳腺癌术后辅助化学药物治疗中加用脾多肽的临床免疫疗效观察[J]. 首都医科大学学报, 2019, 40(3): 443-448.
[15]	陈妮娜, 范怡畅, 尚昆, 杨婧, 曹邦伟. 血清血脂及载脂蛋白浓度与乳腺癌分子分型及Ki-67表达水平的相关性研究[J]. 首都医科大学学报, 2019, 40(2): 191-194.