Chen W Y, Ramamoorthy P, Chen N, Sticca R, Wagner T E
Oncology Research Institute, Cancer Center, Greenville Hospital System, South Carolina 29605, USA.
Clin Cancer Res. 1999 Nov;5(11):3583-93.
Human breast cancer is the predominant malignancy and the leading cause of cancer death in women from Western societies. The cause of breast cancer is still unknown. Recently, the association between human prolactin (hPRL) activity and breast cancer has been reemphasized. Biologically active hPRL has been found to be produced locally by breast cancer cells that contain high levels of PRL receptor. A high incidence of mammary tumor growth has also been found in transgenic mice overexpressing lactogenic hormones. More importantly, it has been demonstrated that the receptors for sex steroids and PRL are coexpressed and cross-regulated. In this study, we report that we have designed and produced a hPRL antagonist, hPRL-G129R. By using cell proliferation assays, we have demonstrated that: (a) hPRL and E2 exhibited an additive stimulatory effect on human breast cancer cell (T-47D) proliferation; (b) hPRL-G129R possessed an inhibitory effect on T-47D cell proliferation; and (c) when antiestrogen (4-OH-tamoxifen) and anti-PRL (hPRL-G129R) agents were added together, an additive inhibitory effect was observed. We further investigated the mechanism of the inhibitory effects of hPRL-G129R in four hPRLR positive breast cancer cell lines. We report that hPRL-G129R is able to induce apoptosis in all four cell lines in a dose-dependent manner as determined by the Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay. The apoptosis is induced within 2 h of treatment at a dose as low as 50 ng/ml. We hope that the hPRL antagonist could be used to improve the outcome of human breast cancer therapy in the near future.
人类乳腺癌是西方社会女性中最主要的恶性肿瘤，也是癌症死亡的主要原因。乳腺癌的病因仍然不明。最近，人类催乳素（hPRL）活性与乳腺癌之间的关联再次受到强调。已发现具有生物活性的hPRL由含有高水平PRL受体的乳腺癌细胞在局部产生。在过表达催乳激素的转基因小鼠中也发现乳腺肿瘤生长的发生率很高。更重要的是，已证明性类固醇和PRL的受体共表达并相互交叉调节。在本研究中，我们报告我们设计并制备了一种hPRL拮抗剂hPRL-G129R。通过细胞增殖试验，我们证明：（a）hPRL和E2对人乳腺癌细胞（T-47D）增殖表现出相加刺激作用；（b）hPRL-G129R对T-47D细胞增殖具有抑制作用；（c）当抗雌激素（4-羟基他莫昔芬）和抗PRL（hPRL-G129R）药物一起添加时，观察到相加抑制作用。我们进一步研究了hPRL-G129R在四种hPRLR阳性乳腺癌细胞系中的抑制作用机制。我们报告，通过末端脱氧核苷酸转移酶介导的dUTP缺口末端标记试验确定，hPRL-G129R能够以剂量依赖的方式在所有四种细胞系中诱导凋亡。在低至50 ng/ml的剂量下，处理2小时内即可诱导凋亡。我们希望hPRL拮抗剂在不久的将来可用于改善人类乳腺癌治疗的效果。
