Shiu R P, Lima G, Leung C K, Dembinski T C
J Steroid Biochem. 1986 Jan;24(1):133-8. doi: 10.1016/0022-4731(86)90042-7.
Although polyamines are important in regulating proliferation of mammalian cells, their role in hormone induction of cell growth has not been delineated. In the estradiol-responsive human breast cancer cell line, T-47D clone 11, estradiol (10(-10) M) was able to stimulate cell proliferation and the activity of ornithine decarboxylase (ODC), the first and rate-limiting enzyme in the biosynthesis of polyamines. alpha-Difluoromethylornithine (DFMO), a specific inhibitor of ODC, blocked the estradiol-induced cell proliferation and ODC activity. Exogenous addition of putrescine, the natural product of ODC, rescued the inhibitory effect of DFMO. In addition, DFMO abolished the estradiol-induced growth of several other estrogen-responsive human breast cancer cell lines but did not affect the growth of hormone-independent cell lines. Further, a serum factor was found to be required for estradiol to exert its effect. To gain insight into the nature of this and possibly other extrinsic factors involved, the effect of estradiol on the proliferation of T-47D cells transplanted into athymic nude mouse was evaluated. In this in vivo system, estradiol alone produced only moderate growth of the human breast tumor. The simultaneous transplantation of a prolactin (PRL)- and growth hormone (GH)-secreting rat pituitary tumor or normal rat pituitary glands at a different site dramatically potentiated the effect of estradiol on the growth of the breast tumor xenograft. Purified PRL or GH were without effect, indicating that the active pituitary factor is neither PRL nor GH. Further, conditioned medium from rat pituitary tumor cells potentiated the mitogenic effect of estradiol on T-47D and several other estrogen receptor-positive human breast cancer cell lines in vitro under serum-free condition. In conclusion, we have identified both intrinsic (polyamines) and extrinsic (pituitary/serum) factors that are importance for estrogen to exert its mitogenic action. The next goal will be to elucidate the mechanisms of action of these molecules in the modulation of estrogen action.
尽管多胺在调节哺乳动物细胞增殖中很重要，但其在激素诱导细胞生长中的作用尚未明确。在雌激素反应性人乳腺癌细胞系T-47D克隆11中，雌二醇（10⁻¹⁰ M）能够刺激细胞增殖以及鸟氨酸脱羧酶（ODC）的活性，ODC是多胺生物合成中的首个限速酶。α-二氟甲基鸟氨酸（DFMO）是ODC的特异性抑制剂，它能阻断雌二醇诱导的细胞增殖和ODC活性。外源性添加腐胺（ODC的天然产物）可挽救DFMO的抑制作用。此外，DFMO消除了雌二醇对其他几种雌激素反应性人乳腺癌细胞系的诱导生长作用，但不影响激素非依赖性细胞系的生长。此外，发现血清因子是雌二醇发挥作用所必需的。为了深入了解这种以及可能涉及的其他外在因素的性质，评估了雌二醇对移植到无胸腺裸鼠体内的T-47D细胞增殖的影响。在这个体内系统中，单独使用雌二醇仅能使人类乳腺肿瘤适度生长。同时在不同部位移植分泌催乳素（PRL）和生长激素（GH）的大鼠垂体肿瘤或正常大鼠垂体，可显著增强雌二醇对乳腺肿瘤异种移植生长的作用。纯化的PRL或GH没有作用，表明活性垂体因子既不是PRL也不是GH。此外，在无血清条件下，大鼠垂体肿瘤细胞的条件培养基在体外增强了雌二醇对T-47D和其他几种雌激素受体阳性人乳腺癌细胞系的促有丝分裂作用。总之，我们已经确定了内在（多胺）和外在（垂体/血清）因素对雌激素发挥其促有丝分裂作用很重要。下一个目标将是阐明这些分子在调节雌激素作用中的作用机制。
