Lundholt B K, Madsen M W, Lykkesfeldt A E, Petersen O W, Briand P
Department of Tumor Endocrinology, Danish Cancer Society, Copenhagen, Denmark.
Mol Cell Endocrinol. 1996 May 17;119(1):47-59. doi: 10.1016/0303-7207(96)03793-8.
Estrogens play an important role in breast cancer and the effect of estrogen on growth of breast cancer cells has been extensively studied. However, only little information is available about the response of normal breast epithelial cells to estrogen, mainly due to the difficulties in establishing estrogen receptor (ER)-positive human breast epithelial cells in culture. We have stably transfected the human estrogen receptor (hER) wt cDNA into the ER-negative, spontaneously immortalized human breast epithelial cell line, HMT-3522S1, in order to develop a model for studying the effect of estrogen on nonmalignant human breast epithelial cells. Characterization of the transfected clone F9 confirmed incorporation of the estrogen receptor gene in the genome, expression of hER mRNA and hER protein. However, proliferation of F9 cells was inhibited by both estradiol (E2) and tamoxifen, whereas the pure antiestrogen ICI 182,780 had no effect on cell proliferation. This seems paradoxical since E2 stimulated the expression of the endogenous genes, TGF-alpha, cathepsin D, and alpha1-antitrypsin. In breast cancer cell lines, high expression of these genes is correlated to estrogen-stimulated cell proliferation. The spontaneously immortalized HMT-3522S1 cells transfected with wt ER cDNA behave similarly to cell lines from nonmalignant breast tissue immortalized by carcinogens and transfected with mutated ER cDNA as described by others. The discrepancy between growth inhibition and induction of positive growth factors by E2 indicates that either ER-positive nonmalignant breast epithelial cells are growth-inhibited by E2 in contrast to malignant cells or that introduction of the ER into ER-negative cells is not sufficient for restoring "normal' estrogen responsiveness.
雌激素在乳腺癌中发挥着重要作用，并且雌激素对乳腺癌细胞生长的影响已得到广泛研究。然而，关于正常乳腺上皮细胞对雌激素的反应，目前仅有少量信息，这主要是由于在培养中建立雌激素受体（ER）阳性的人乳腺上皮细胞存在困难。我们已将人雌激素受体（hER）野生型cDNA稳定转染至ER阴性、自发永生化的人乳腺上皮细胞系HMT - 3522S1中，以建立一个研究雌激素对非恶性人乳腺上皮细胞作用的模型。对转染克隆F9的特性分析证实雌激素受体基因已整合到基因组中，hER mRNA和hER蛋白均有表达。然而，雌二醇（E2）和他莫昔芬均抑制F9细胞的增殖，而纯抗雌激素药物ICI 182,780对细胞增殖无影响。这似乎自相矛盾，因为E2刺激了内源性基因TGF -α、组织蛋白酶D和α1 -抗胰蛋白酶的表达。在乳腺癌细胞系中，这些基因的高表达与雌激素刺激的细胞增殖相关。用野生型ER cDNA转染的自发永生化HMT - 3522S1细胞的行为与其他人所描述的用致癌物永生化并转染了突变型ER cDNA的非恶性乳腺组织细胞系类似。E2对生长的抑制作用与对正向生长因子的诱导作用之间的差异表明，要么ER阳性的非恶性乳腺上皮细胞与恶性细胞相反，被E2抑制生长，要么将ER导入ER阴性细胞不足以恢复“正常”的雌激素反应性。
