Wright Jay W, Stouffer Richard L, Rodland Karin D
Oregon Regional Primate Research Center, Division of Reproductive Sciences, 505 NW 185th Ave, Beaverton, OR 97006, USA.
Mol Cell Endocrinol. 2003 Oct 31;208(1-2):1-10. doi: 10.1016/j.mce.2003.08.001.
Estrogen promotes the growth of some ovarian cancer cells at nanomolar concentrations, but has been shown to inhibit growth of normal ovarian surface epithelial (OSE) cells at micromolar concentrations (1 microg/ml). OSE cells express the estrogen receptor (ER)-alpha, and are the source of 90% of ovarian cancers. The potential sensitivity of OSE cells to estrogen stresses the importance of understanding the estrogen-dependent mechanisms at play in OSE proliferation and transformation, as well as in anticancer treatment. We investigated the effects of estradiol on cell proliferation in vitro, and demonstrate an intracellular locus of action of estradiol in cultured rhesus ovarian surface epithelial (RhOSE) cells. We show that ovarian and breast cells are growth-inhibited by micromolar concentrations of estradiol, and that this inhibition correlates with estrogen receptor expression. We further show that normal rhesus OSE cells do not activate ERK or Akt in response to estradiol, nor does estradiol block the ability of serum to stimulate ERK or induce cyclin D expression. Contrarily, estradiol inhibits serum-dependent retinoblastoma protein (Rb) phosphorylation and blocks DNA synthesis. This inhibition does not formally arrest cells, and is reversible within hours of estrogen withdrawal. Our data are consistent with growth inhibition by activation of Rb and indicate that sensitivity to hormone therapy in anticancer treatment can be modulated by cell cycle regulators downstream of the estrogen receptor.
雌激素在纳摩尔浓度下可促进某些卵巢癌细胞的生长，但已表明在微摩尔浓度（1微克/毫升）时会抑制正常卵巢表面上皮（OSE）细胞的生长。OSE细胞表达雌激素受体（ER）-α，并且是90%卵巢癌的起源。OSE细胞对雌激素的潜在敏感性强调了理解雌激素依赖性机制在OSE增殖、转化以及抗癌治疗中所起作用的重要性。我们研究了雌二醇对体外细胞增殖的影响，并证明了雌二醇在培养的恒河猴卵巢表面上皮（RhOSE）细胞中的细胞内作用位点。我们表明，微摩尔浓度的雌二醇会抑制卵巢和乳腺细胞的生长，并且这种抑制作用与雌激素受体表达相关。我们进一步表明，正常的恒河猴OSE细胞不会因雌二醇而激活ERK或Akt，雌二醇也不会阻断血清刺激ERK或诱导细胞周期蛋白D表达的能力。相反，雌二醇会抑制血清依赖性视网膜母细胞瘤蛋白（Rb）的磷酸化并阻断DNA合成。这种抑制作用不会正式使细胞停滞，并且在撤除雌激素后的数小时内是可逆的。我们的数据与通过激活Rb来抑制生长一致，并表明雌激素受体下游的细胞周期调节因子可调节抗癌治疗中对激素疗法的敏感性。
