Schneider H P, Jackisch C
Department of Obstetrics and Gynecology, University of Muenster, Germany.
Int J Fertil Womens Med. 1998 Nov-Dec;43(6):278-85.
The mammary gland seems to be the only organ that is not fully developed at birth. Estrogens stimulate breast tissue via estrogen receptors (ERs). In the mammary gland, ER-mediated mechanisms have been shown to regulate: various growth factors, such as TGF-alpha and TGF-beta; enzymes, such as cathepsin D and plasminogen-activator; proto-oncogenes, such as c-fos, c-myc and HER-2/neu; cyclines and other regulatory substances that provide signaling systems for cell division and differentiation; other steroid receptors and epidermal growth factor receptors. Estrogen target genes contain estrogen-responsive elements. In these genes, transcription will be activated through interaction with the estrogen/ER protein complex. Subsequent activation of proto-oncogenes provides an explanation for the stimulating effect of estrogens on the glandular breast. Progesterone may be the key in influencing the risk of breast cancer with the peak of mitotic activity in the breast during the luteal phase of the menstrual cycle. On the other hand, in human breast cancer cell lines, both proliferation and inhibition have been observed with various progestational agents. Relevant biological and clinical issues are pregnancy and exposure to exogenous hormones. The intense hormonal stimulation of pregnancy (both estrogen and progesterone) has no adverse impact on the course of breast cancer. Pregnancy, with its mammogenetic differentiation, results in the protection of this organ from carcinogenesis. Characterization of specific lobular morphology serves as an indicator of the level of differentiation achieved by the organ, and thus provides means to assess the risk of the gland undergoing neoplastic transformation when exposed to given agents. Sufficient evidence exists to indicate the possibility of a slightly increased risk of breast cancer after approximately one decade of postmenopausal estrogen use. A review of the epidemiologic studies of postmenopausal hormone replacement and the risk of breast cancer fails to provide definitive evidence. Recent information derives from observations of cellular proliferation, plasma and tissue estradiol and progesterone receptor levels, and the percentage of apoptotic epithelial cells in human breast tissue. Several studies suggest that short-term, continuous combined HRT does not increase breast cancer recurrence or mortality. The participation of sexual hormones in the mammogenetic process during pregnancy might serve as an intermediate end point in assessing the effectiveness of hormones as chemopreventive agents. Investigations based on history, and breast morphology, should enable us to select estrogens and progestogens for HRT, and adopt optimal therapeutic regimens.
乳腺似乎是出生时唯一未完全发育的器官。雌激素通过雌激素受体（ERs）刺激乳腺组织。在乳腺中，已表明ER介导的机制可调节：多种生长因子，如转化生长因子-α（TGF-α）和转化生长因子-β（TGF-β）；酶，如组织蛋白酶D和纤溶酶原激活剂；原癌基因，如c-fos、c-myc和HER-2/neu；细胞周期蛋白和其他为细胞分裂和分化提供信号系统的调节物质；其他类固醇受体和表皮生长因子受体。雌激素靶基因含有雌激素反应元件。在这些基因中，转录将通过与雌激素/ER蛋白复合物的相互作用而被激活。原癌基因的后续激活为雌激素对乳腺的刺激作用提供了解释。孕酮可能是影响乳腺癌风险的关键因素，在月经周期的黄体期，乳腺有丝分裂活动达到峰值。另一方面，在人乳腺癌细胞系中，使用各种孕激素制剂时既观察到了增殖也观察到了抑制作用。相关的生物学和临床问题是妊娠和接触外源性激素。妊娠期间强烈的激素刺激（雌激素和孕酮）对乳腺癌的病程没有不利影响。妊娠及其乳腺发生分化可使该器官免受致癌作用。特定小叶形态的特征可作为该器官分化程度的指标，从而为评估该腺体在接触特定制剂时发生肿瘤转化的风险提供方法。有充分证据表明，绝经后使用雌激素约十年后，患乳腺癌的风险可能略有增加。对绝经后激素替代与乳腺癌风险的流行病学研究进行综述未能提供确凿证据。最新信息来自对细胞增殖、血浆和组织雌二醇及孕酮受体水平以及人乳腺组织中凋亡上皮细胞百分比的观察。几项研究表明，短期、持续联合激素替代疗法不会增加乳腺癌复发率或死亡率。性激素在妊娠期间乳腺发生过程中的参与可能作为评估激素作为化学预防剂有效性的中间终点。基于病史和乳腺形态的研究应使我们能够选择用于激素替代疗法的雌激素和孕激素，并采用最佳治疗方案。
