Mukherjee S, Louie S G, Campbell M, Esserman L, Shyamala G
Division of Life Sciences, Lawrence Berkeley National Laboratory, University of California, Berkeley 94720, USA.
Oncogene. 2000 Dec 7;19(52):5982-7. doi: 10.1038/sj.onc.1203964.
The steroid hormone, estradiol, is essential for both the growth of normal breast and induction of mammary carcinomas. The growth promoting effects of estrogen are presumed to be mediated by growth factors, in particular, epidermal growth factor, which mediates its effects through erbB receptors, erbB1 and erbB2/C-neu. C-neu is amplified and over-expressed in a large number of human cancers and transgenic mice over-expressing C-neu also develop mammary tumors. However, as yet, the impact of C-neu over-expression on estrogen action during normal mammary development and hence, its precise role in carcinogenesis, remains unclear. In the present studies, we demonstrate that estradiol-dependent mammary ductal growth accompanying puberty is impaired in transgenic mice expressing wild type Cneu, and is intrinsic to the tissue. The impairment is not due to an overall impairment in estrogen action, since progesterone receptor expression is unaffected in C-neu mice. It is also not due to an intrinsic inability of the epithelial cells to proliferate, since impeded ductal growth co-exists with alveolar growth during pregnancy. Therefore, we propose that, depending on the physiological state, C-neu may either promote or inhibit the growth of mammary epithelial cells, and discuss its potential significance to carcinogenesis.
类固醇激素雌二醇对正常乳腺的生长和乳腺癌的诱发均至关重要。雌激素的促生长作用据推测是由生长因子介导的，尤其是表皮生长因子，它通过erbB受体erbB1和erbB2/C-neu介导其作用。C-neu在大量人类癌症中扩增并过度表达，过度表达C-neu的转基因小鼠也会发生乳腺肿瘤。然而，迄今为止，C-neu过度表达在正常乳腺发育过程中对雌激素作用的影响，以及因此其在致癌作用中的精确作用仍不清楚。在本研究中，我们证明，在表达野生型Cneu的转基因小鼠中，伴随青春期的雌二醇依赖性乳腺导管生长受损，且这种损伤是组织固有的。这种损伤并非由于雌激素作用的整体受损，因为C-neu小鼠中的孕激素受体表达未受影响。这也不是由于上皮细胞增殖的内在能力不足，因为在怀孕期间，导管生长受阻与腺泡生长并存。因此，我们提出，根据生理状态，C-neu可能促进或抑制乳腺上皮细胞的生长，并讨论了其对致癌作用的潜在意义。
