Effects of estrogens and antiestrogens on estrogen receptor dynamics and the induction of progesterone receptor in MCF-7 human breast cancer cells.
Effects of estrogens and antiestrogens on estrogen receptor dynamics and the induction of progesterone receptor in MCF-7 human breast cancer cells.
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发表时间：
1982
期刊：
影响因子：
11.2
通讯作者：
R. Eckert;B. Katzenellenbogen
中科院分区：
文献类型：
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作者：
R. Eckert;B. Katzenellenbogen
摘要抗雌激素似乎在治疗人类内分泌反应性乳腺癌方面是有用的。为了了解它们与乳腺癌细胞的相互作用，我们研究了雌激素(雌二醇和己烯雌酚)和一系列雌激素受体(ER)亲和力的抗雌激素对MCF-7人乳腺癌细胞内ER动力学和生物反应(孕激素受体)诱导的影响。所研究的三苯乙烯类抗雌激素药物为：-[2-(1-pyrrolidino)ethoxy]phenyl}-4-methoxy-α′-nitrostilbene-{p--[2-(1-pyrrolidino)ethoxy]phenyl}-4-hydroxy-α′-nitrostilbene(CI628)，-tetrahydro-6-methoxy-2-phenyl-1-naphthyl)phenoxy]-1，2-propanediol}-{p-(1，2，3，4，α)，α-{3-[p-(1，2，3，4，U23,469)]和顺-{3-[p-(1，2，2，3，4-tetrahydro-6-hydroxy-2-phenyl-1-naphthyl)phenoxy]-1，2，丙二醇(U23,469M)。抗雌激素CI628、CI628M、U23、469和U23、469M与细胞质雌激素受体(ERC)的相对结合亲和力分别为1.0、17、0.04和34%，其中雌二醇亲和力为100%。受体饱和浓度的CI628、CI628M、雌二醇和己烯雌酚(分别为200、10、10和10 nM)在1小时内引起ERC的完全耗竭和核内ER的高峰积累。核受体(ERN)的位置随后下降，并在2至5小时内稳定在接近控制的水平(每毫克DNA 1.2pmolERN)，导致新的损失(处理)约50%的细胞总ER。相反，U23,469(2000 NM)促进ERN在5min内完全耗尽ERC和数量积累，但ER总量在此后保持不变(不处理)。U23,469M(60 NM)促进ERC的完全耗竭和数量的核积累，但ERN的数量随后缓慢下降，到第5天时达到对照水平。其中，雌二醇和己烯雌酚(0.1~1000 nM)促进细胞浆孕酮受体增加600%(5天，对照=0.2pmol/mgDNA)。Cl628M和U23,469M(1-10 nm)仅促进了300%的增长，而U23,469和Cl628(0.1-1000 nm)没有促进任何增加。这些结果表明：(A)ER向细胞核的移位和孕激素受体的诱导似乎与配体亲和力有关；(B)抗雌激素与ER相互作用的动力学和刺激细胞孕酮受体增加的能力可能存在很大差异；(C)抗雌激素如CI628对ER的处理并不能确保随后孕激素受体的诱导；以及(D)在细胞核中激素受体复合体的存在和持续时间与MCF-7细胞孕激素受体的诱导之间存在明显的复杂关系。由于四种抗雌激素都抑制MCF-7细胞的生长，但它们提高细胞孕激素受体水平的能力不同，这些研究表明，在这些人乳腺癌细胞中，生长和孕激素受体诱导是独立受抗雌激素调节的现象。
Abstract Antiestrogens appear to be useful in the treatment of endocrine-responsive breast cancers in humans. In an attempt to understand their interactions with breast cancer cells, we have examined the effects of estrogens (estradiol and diethylstilbestrol), and antiestrogens with a range of affinities for estrogen receptor (ER), on intracellular ER dynamics and biological response (progesterone receptor) induction in MCF-7 human breast cancer cells. The triphenylethylene antiestrogens studied are α-{ p -[2-(1-pyrrolidino)ethoxy]phenyl}-4-methoxy-α′-nitrostilbene (CI628), α-{ p -[2-(1-pyrrolidino)ethoxy]phenyl}-4-hydroxy-α′-nitrostilbene (CI628M), cis -{3-[p-(1,2,3,4,-tetrahydro-6-methoxy-2-phenyl-1-naphthyl)phenoxy]-1,2-propanediol} (U23,469), and cis -{3-[p-(1,2,3,4-tetrahydro-6-hydroxy-2-phenyl-1-naphthyl)phenoxy]-1,2,propanediol} (U23,469M). The relative binding affinities of the antiestrogens CI628, CI628M, U23,469, and U23,469M for cytoplasmic ER (ERC) were 1.0, 17, 0.04, and 34%, respectively, in which the affinity of estradiol is considered 100%. Receptor-saturating concentrations of CI628, CI628M, estradiol, and diethylstilbestrol (200, 10, 10, and 10 nM, respectively) caused complete ERC depletion and peak nuclear ER accumulation within 1 hr. The nuclear receptor (ERN) sites declined thereafter and stabilized at near-control levels (1.2 pmol ERN per mg DNA) by 2 to 5 hr, resulting in a new loss (processing) of approximately 50% of total cellular ER. In contrast, U23,469 (2000 nM) promoted complete depletion of ERC and quantitative accumulation as ERN within 5 min, but the total ER content remained constant thereafter (no processing). U23,469M (60 nM) promoted complete ERC depletion and quantitative nuclear accumulation, but the number of ERN sites subsequently declined slowly to reach the control level by Day 5. Among these compounds, estradiol and diethylstilbestrol (0.1 to 1000 nM) promoted a 600% increase in cytoplasmic progesterone receptor (5 days, control = 0.2 pmol/mg DNA). Cl628M and U23,469M (1 to 10 nM) produced only a 300% increase, and U23,469 and Cl628 (0.1 to 1000 nM) did not promote any increase. These results indicate that: ( a ) ER translocation to the nucleus and progesterone receptor induction appear to be related to ligand affinity; ( b ) antiestrogens can differ substantially from one another in their dynamics of interaction with ER and in their abilities to stimulate increases in cellular progesterone receptor; ( c ) processing of ER by antiestrogens such as CI628 does not ensure subsequent induction of progesterone receptor; and ( d ) an apparently complex relationship exists between the presence and duration of hormone receptor complexes in the nucleus and the induction of progesterone receptor in MCF-7 cells. Since all four antiestrogens inhibit MCF-7 cell growth but differ in their ability to increase cellular progesterone receptor levels, these studies indicate that growth and progesterone receptor induction are phenomena that are independently modulated by antiestrogens in these human breast cancer cells.