HER-2 tyrosine kinase pathway targets estrogen receptor and promotes hormone-independent growth in human breast cancer cells.
HER-2 tyrosine kinase pathway targets estrogen receptor and promotes hormone-independent growth in human breast cancer cells.
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发表时间：
1995-06
期刊：
影响因子：
8
通讯作者：
R. Pietras;M. Arboleda;Reese Dm;N. Wongvipat;Pegram;Lillian Ramos;C. Gorman;Parker Mg;M. Sliwkowski;D. Slamon
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文献类型：
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作者：
R. Pietras;M. Arboleda;Reese Dm;N. Wongvipat;Pegram;Lillian Ramos;C. Gorman;Parker Mg;M. Sliwkowski;D. Slamon
人类乳腺细胞的生长受到类固醇激素和肽类激素受体的密切调节。这两种受体类型的成员是人类乳腺癌的重要预后因素。临床数据表明HER-2基因的过表达与雌激素受体阴性表型相关。在这项研究中，我们证明了HER-2 cDNA的引入，将非过表达的乳腺癌细胞转化为过表达这种受体的细胞，导致雌激素非依赖性生长的发展，这种生长对雌激素和抗雌激素药物他莫昔芬都不敏感。此外，乳腺癌细胞中HER-2受体被肽生长因子heregulin激活，导致ER在酪氨酸残基上直接和快速磷酸化。随后是ER和细胞核中的雌激素反应元件之间的相互作用，并产生雌激素诱导的蛋白质孕酮受体。此外，HER-2受体在雌激素依赖性肿瘤细胞中的过表达促进了ER的配体非依赖性下调和ER转录物的延迟的自身调节抑制。这些数据证明了这两种受体途径之间的直接联系，并提出了人类乳腺癌内分泌耐药性发展的一种机制。
Growth of human breast cells is closely regulated by steroid hormone as well as peptide hormone receptors. Members of both receptor classes are important prognostic factors in human breast cancer. Clinical data indicate that overexpression of the HER-2 gene is associated with an estrogen receptor-negative phenotype. In this study, we demonstrate that introduction of a HER-2 cDNA, converting non-overexpressing breast cancer cells to those which overexpress this receptor, results in development of estrogen-independent growth which is insensitive to both estrogen and the antiestrogen, tamoxifen. Moreover, activation of the HER-2 receptor in breast cancer cells by the peptide growth factor, heregulin, leads to direct and rapid phosphorylation of ER on tyrosine residues. This is followed by interaction between ER and the estrogen-response elements in the nucleus and production of an estrogen-induced protein, progesterone receptor. In addition, overexpression of HER-2 receptor in estrogen-dependent tumor cells promotes ligand-independent down-regulation of ER and a delayed autoregulatory suppression of ER transcripts. These data demonstrate a direct link between these two receptor pathways and suggest one mechanism for development of endocrine resistance in human breast cancers.