Pathogenesis of Paget's disease:: Epidermal heregulin-α, motility factor, and the HER receptor family
Pathogenesis of Paget's disease:: Epidermal heregulin-α, motility factor, and the HER receptor family
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DOI：
10.1093/jnci/92.8.622
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发表时间：
2000-04-19
影响因子：
10.3
通讯作者：
De Potter, CR
中科院分区：
文献类型：
--
作者：
Schelfhout, VRJ;Coene, ED;De Potter, CR
背景和方法：在Paget病的乳房？乳头的表皮被腺体起源的大的肿瘤细胞所侵袭。有人假设，Paget细胞通过乳头表皮扩散是由一种运动因子诱导的，该因子通过HER2/neu受体发挥作用。为了验证这一假说，我们鉴定和纯化了角质形成细胞释放的一种运动因子，并在Paget病患者的标本和过度表达HER2/neu的SK-BR3乳腺腺癌细胞中鉴定了其靶受体。结果：我们从角质形成细胞条件培养液中分离到了运动因子，并对其进行了序列测定，结果表明该运动因子是由皮肤角质形成细胞释放的，与运动因子一样，它能诱导SK-BR3细胞的扩散、运动和趋化。针对HER2/neu胞外区的单抗AB2可抑制HER2-α的运动因子活性，从而阻断HER2-α的结合。我们用原位杂交的方法证明了正常的表皮细胞产生HERG-α信使RNA，并且HER3和/或HER4及其辅助受体HER2/neu在Paget细胞中表达。结论：HERG-α是一种由正常表皮角质形成细胞产生和释放的运动性因子，在Paget病的发病机制中起关键作用。Paget细胞表达HER2/neu受体，以及HER3和/或HER4，两者都是HER2/neu的共同受体。黑素-α与Paget细胞上的受体复合体结合，导致这些乳腺癌细胞的趋化，最终迁移到覆盖乳头的表皮。
Background and Methods: In Paget's disease of the breast? the epidermis of the nipple is infiltrated by large neoplastic cells of glandular origin. It has been hypothesized that the spread of Paget cells through the nipple epidermis is induced by a motility factor that acts via the HER2/NEU receptor. To test this hypothesis, we characterized and purified a motility factor released by keratinocytes and identified its target receptors in specimens from patients with Paget's disease and in SK-BR3 breast adenocarcinoma cells, which overexpress HER2/NEU. Results: We isolated the motility factor from keratinocyte-conditioned medium and sequenced tryptic peptides, These sequences were used to identify the motility factor as heregulin-alpha, which is released by skin keratinocytes, Heregulin-alpha induces spreading, motility, and chemotaxis of SK-BR3 cells, as does motility factor. Motility factor activities of heregulin-alpha are inhibited by monoclonal antibody AB2, directed against the extracellular domain of HER2/NEU, which blocks the binding of heregulin-alpha. We used in situ hybridization to show that normal epidermal cells produce heregulin-alpha messenger RNA and that heregulin receptors, HER3 and/or HER4, as well as their coreceptor HER2/NEU, are expressed by Paget cells. Conclusions: Heregulin-alpha is a motility factor that is produced and released by normal epidermal keratinocytes and thus plays a key role in the pathogenesis of Paget's disease. Paget cells express heregulin receptors HER2/NEU, as well as HER3 and/or HER4, both of which function as a co-receptor of HER2/NEU. Binding of heregulin-alpha to the receptor complex on Paget cells results in the chemotaxis of these breast cancer cells, which eventually migrate into the overlying nipple epidermis.