Prolactin induces ERα-positive and ERα-negative mammary cancer in transgenic mice
Prolactin induces ERα-positive and ERα-negative mammary cancer in transgenic mice
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DOI：
10.1038/sj.onc.1206619
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发表时间：
2003-07-24
期刊：
影响因子：
8
通讯作者：
Schuler, LA
中科院分区：
文献类型：
--
作者：
Rose-Hellekant, TA;Arendt, LM;Schuler, LA
催乳素在人类乳腺癌中的作用一直存在争议。然而，现在很明显，人类乳腺上皮细胞可以内源性合成催乳素，允许乳腺内独立于垂体催乳素的自分泌/旁分泌活动。为了模拟局部乳腺产生催乳素(PRL)，我们培育了在荷尔蒙无反应启动子NeuRelated Lipocalin(NRL)控制下在乳腺上皮细胞内过表达催乳素的小鼠。在两个被检测的NRL-PRL转基因小鼠谱系中，雌性处女鼠都表现出乳腺发育异常、乳腺上皮内肿瘤和侵袭性肿瘤。催乳素促进形态正常的肺泡和导管以及皮损中的增殖。肿瘤的组织类型多种多样，但以乳头状腺癌和腺鳞癌为主。肿瘤可分为两类：一类是雌激素受体α(ERpha)阳性(超过细胞染色的15%)，另一类是ERpha-(3%)。ERα的表达与肿瘤组织类型、增殖指数或凋亡指数无关。这些研究提供了荷尔蒙依赖性乳腺癌的小鼠模型，也许最引人注目的是，一些肿瘤保留了ERA，就像人类疾病中发生的那样。
The role of prolactin in human breast cancer has been controversial. However, it is now apparent that human mammary epithelial cells can synthesize prolactin endogenously, permitting autocrine/paracrine actions within the mammary gland that are independent of pituitary prolactin. To model this local mammary production of prolactin (PRL), we have generated mice that overexpress prolactin within mammary epithelial cells under the control of a hormonally nonresponsive promoter, neurelated lipocalin (NRL). In each of the two examined NRL-PRL transgenic mouse lineages, female virgin mice display mammary developmental abnormalities, mammary intraepithelial neoplasias, and invasive neoplasms. Prolactin increases proliferation in morphologically normal alveoli and ducts, as well as in lesions. The tumors are of varied histotype, but papillary adenocarcinomas and adenosquamous neoplasms predominate. Neoplasms can be separated into two populations: one is estrogen receptor alpha (ERalpha) positive (greater than 15% of the cells stain for ERalpha), and the other is ERalpha- ( < 3%). ER alpha expression does not correlate with tumor histotype, or proliferative or apoptotic indices. These studies provide a mouse model of hormonally dependent breast cancer, and, perhaps most strikingly, a model in which some neoplasms retain ERa, as occurs in the human disease.