PROLACTIN RECEPTOR ANTAGONISTS THAT INHIBIT THE GROWTH OF BREAST-CANCER CELL-LINES
PROLACTIN RECEPTOR ANTAGONISTS THAT INHIBIT THE GROWTH OF BREAST-CANCER CELL-LINES
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DOI：
10.1074/jbc.270.22.13133
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发表时间：
1995-06-02
影响因子：
4.8
通讯作者：
WELLS, JA
中科院分区：
文献类型：
--
作者：
FUH, G;WELLS, JA
我们研究了人催乳素 (hPRL) 受体对四种不同乳腺癌细胞系 T-47D、MCF-7、BT-474 和 SK-BR3 的作用机制，与正常细胞相比，这些细胞系表达的受体水平升高。用结合并激活 hPRL 受体的人生长激素 (hGH) 处理的细胞表现出钟形剂量反应生长曲线，与针对 hPRL 受体提出的顺序二聚化机制一致 (Fuh, G., Colosi, P., Wood, W.I., and Wells, J.A. (1995) J. Biol. Chem. 268, 5376-5381)。 Zn2+ 可增强生长刺激，优先增加 hGH 对 hPRL 受体的亲和力。此外，结合 hPRL 受体但不结合 hGH 受体的 hGH 受体选择性变体具有激动性，这为与 hPRL 受体的特异性结合可以刺激这些乳腺癌细胞生长提供了额外的支持。在此基础上，我们生产了 hGH 和人胎盘催乳素 (hPL) 的变体，它们是潜在的拮抗剂，因为它们结合但不二聚化 hPRL 受体。基于 hPL 的拮抗剂对 MCF-7 细胞生长的作用不如基于 hGH 的拮抗剂，这与 hPL 对 hPRL 受体的亲和力低于对 hGH 的亲和力一致。然而，对于 BT-474 细胞，基于 hPL 的拮抗剂比 hGH 拮抗剂更有效。 hPRL受体抗体抑制转染hPRL受体的FDC-P1细胞的生长；这些还抑制 MCF-7 细胞和 T47D 细胞，但不抑制 BT-474 细胞。当筛选 BT-474 细胞的 cDNA 时，发现了 BT-474 细胞的一个独特特征，即存在编码可溶性胞外结构域的 hPRL 受体的新型选择性剪接；这可以解释这些不同的抑制作用。这些研究为 hPRL 受体在乳腺癌中的潜在作用提供了进一步的分子见解，并证明 hPRL 受体拮抗剂可以抑制乳腺癌细胞的生长。
We investigated the mechanism of action of the human prolactin (hPRL) receptor on four different breast cancer cell lines, T-47D, MCF-7, BT-474, and SK-BR3, that express elevated levels of the receptor compared with normal cells. Cells treated with human growth hormone (hGH), which binds and activates the hPRL receptor, exhibited bell-shaped dose-response growth curves consistent with the sequential dimerization mechanism proposed for the hPRL receptor (Fuh, G., Colosi, P., Wood, W.I., and Wells, J.A. (1995) J. Biol. Chem. 268, 5376-5381). Growth stimulation was enhanced by Zn2+ which preferentially increases the affinity of hGH for the hPRL receptor. Furthermore, receptor-selective variants of hGH that bind the hPRL receptor but not the hGH receptor were agonistic, providing additional support that specific binding to the hPRL receptor can stimulate these breast cancer cells to grow. On this basis we produced variants of hGH and human placental lactogen (hPL) that were potential antagonists because they bind but do not dimerize the hPRL receptor. The hPL-based antagonist was less potent than the hGH-based antagonist toward the growth of MCF-7 cells, consistent with the lower affinity of hPL for hPRL receptor than for hGH. However, the hPL-based antagonist was more potent than the hGH antagonist for BT-474 cells. Antibodies to the hPRL receptor inhibited growth of FDC-P1 cells transfected with the hPRL receptor; these also inhibited MCF-7 cells and T47D cells but not BT-474 cells. A unique feature of BT-474 cells was found when screening its cDNA revealed the presence of a novel alternative splice of the hPRL receptor that codes for the soluble extracellular domain; this may explain these differential inhibitory effects. These studies provide further molecular insight into the potential role of the hPRL receptor in breast cancer and demonstrate that hPRL receptor antagonists can inhibit the growth of breast cancer cells.