Shyamala Gopalan, Chou Yu-Chien, Cardiff Robert D, Vargis Elizabeth
Lawrence Berkeley National Laboratory, Life Sciences Division, University of California, Berkeley, California, 94720, USA.
Cancer Res. 2006 Nov 1;66(21):10391-8. doi: 10.1158/0008-5472.CAN-06-0321.
Mammary development and tumorigenesis are profoundly influenced by signaling pathways under the control of c-erbB2/c-neu and estrogen receptor alpha (ERalpha). Signaling through ERalpha is essential for ductal growth during puberty. In mice overexpressing wild-type c-neu in mammary epithelial cells, Tg (c-neu), ductal growth is impaired. An impeded signaling through ERalpha is also observed in a subset of human mammary tumors that overexpress erbB2. However, ductal growth is also impaired in the absence of c-neu in mouse mammary epithelial cells. To resolve this apparent paradox, we examined the relationship between c-neu expression and estrogen/ERalpha-dependent cell proliferation in pubertal Tg (c-neu). We report that proliferation in both terminal end buds and ducts is associated with ERalpha-positive cells, including those that coexpress c-neu, and is abolished in the absence of circulating estradiol. Tg (c-neu) contains hyperplastic mammary ducts with high proliferative index and coexpression of both ERalpha and c-neu in the dividing cells. These findings suggest that c-neu promotes ERalpha-dependent proliferation, and that this is responsible for the presence of hyperplastic ducts. Some of the hyperplastic ducts have acinar structures, indicative of morphologic differentiation. These ducts have low proliferative index and accompanied by a vast decrease in proliferation of ERalpha-positive cells, including those that express c-neu. As such, c-neu has dual but opposing effects on ERalpha-dependent proliferation in mammary epithelial cells. Therefore, depending on the physiologic setting, ductal morphogenesis will be compromised both in the absence and overexpression of c-neu, thus explaining the paradox.
乳腺发育和肿瘤发生受到c-erbB2/c-neu和雌激素受体α（ERα）控制的信号通路的深刻影响。通过ERα的信号传导对于青春期导管生长至关重要。在乳腺上皮细胞中过表达野生型c-neu的小鼠（Tg (c-neu)）中，导管生长受损。在过表达erbB2的一部分人类乳腺肿瘤中也观察到通过ERα的信号传导受阻。然而，在小鼠乳腺上皮细胞中缺乏c-neu时，导管生长也会受损。为了解决这一明显的矛盾，我们研究了青春期Tg (c-neu)中c-neu表达与雌激素/ERα依赖性细胞增殖之间的关系。我们报告，终末芽和导管中的增殖与ERα阳性细胞有关，包括那些共表达c-neu的细胞，并且在缺乏循环雌二醇时增殖被消除。Tg (c-neu)包含具有高增殖指数的增生性乳腺导管，并且在分裂细胞中共表达ERα和c-neu。这些发现表明，c-neu促进ERα依赖性增殖，并且这是增生性导管存在的原因。一些增生性导管具有腺泡结构，表明存在形态分化。这些导管具有低增殖指数，并伴随着包括表达c-neu的细胞在内的ERα阳性细胞增殖的大幅下降。因此，c-neu对乳腺上皮细胞中ERα依赖性增殖具有双重但相反的作用。因此，根据生理环境，在缺乏和过表达c-neu时导管形态发生都会受到损害，从而解释了这一矛盾。
