Nestin: A Putative Marker of a Mammary Stem and Progenitor Cell Lineage

描述（由申请人提供）：目前关于肿瘤形成和进展的潜在生物学假设是：1)干细胞和祖细胞是转化突变的靶标；2)存在癌症干细胞，它们具有无限的增殖潜力。正常干细胞和癌症干细胞都具有自我更新的能力，并且被认为利用类似的途径进行自我更新、增殖和命运决定。因此，鉴定乳腺中干细胞和祖细胞的能力对于未来研究这些细胞中的转化事件如何导致特定类型的乳腺癌以及理解调节这些细胞增殖的途径至关重要。人类乳腺组织和乳腺癌中干细胞和祖细胞的鉴定是当前研究的一个活跃领域。然而，尽管在人类乳腺和小鼠乳腺组织中已经描述了干细胞/祖细胞的多种特征，但没有明确的细胞标记可用于识别乳腺/乳腺组织中特定的干细胞和早期祖细胞群体。巢蛋白是一种中间纤维，最初被确定为神经上皮干细胞的标记物。近年来，在多种组织的干细胞/祖细胞中发现了巢蛋白表达，并被认为是干细胞和祖细胞的一般标记物。我们现在有初步的证据表明，巢蛋白在小鼠乳腺中识别出一小部分细胞，其表达模式与其在干细胞和祖细胞群体中的表达一致。此外，我们发现巢蛋白阳性细胞在特定类型的wnt诱导的乳腺肿瘤中扩增。本应用的目的是验证巢蛋白表达识别在某些乳腺肿瘤中扩增的正常乳腺中自我更新的干细胞/祖细胞群的假设。这项研究将阐明乳腺上皮细胞亚群的新标记物，这些细胞在正常乳腺发育过程中有可能产生特定类型的细胞和特定类型的乳腺肿瘤。这种新的标记物可以识别未分化的乳腺肿瘤干细胞或祖细胞群。

DESCRIPTION (provided by applicant): Current hypotheses concerning the underlying biology of tumor formation and progression are that 1) stem and progenitor cells are targets of transforming mutations and, 2) cancer stem cells exist, which have unlimited proliferative potential. Normal stem cells and cancer stem cells both have the ability to self-renew and are thought to utilize similar pathways for self-renewal, proliferation and fate decisions. Thus, the ability to identify stem and progenitor cells in the breast is critical for future investigations of how transforming events in these cells lead to specific types of breast cancers and for understanding the pathways that regulate proliferation of these cells. The identification of stem and progenitor cells in human breast tissue and breast cancers is an active area of current investigation. However, while multiple characteristics of stem/progenitor cells have been described in human breast and mouse mammary tissue, there are no clear cellular markers available to identify specific stem and early progenitor populations in mammary/breast tissue. Nestin is an intermediate filament, which was originally identified as a marker for neuroepithelial stem cells. Recently, nestin expression was identified in the stem/progenitor cells of multiple tissues and has been proposed as a general marker of stem and progenitor cells. We now have preliminary evidence that nestin identifies a small population'of cells in the mouse mammary gland, in a pattern consistent with its expression in stem and progenitor populations. Moreover, we have found that nestin-positive cells are expanded in specific types of Wnt-induced mammary tumors. The goal of this application is to test the hypothesis that nestin expression identifies a population of self-renewing stem/progenitor cells in the normal mammary gland that are expanded in certain mammary tumors. This research will elucidate a new marker for a subset of breast epithelial cells which have the potential to give rise to specific cell types during normal breast development and to specific types of breast tumors. This novel marker may identify a population of undifferentiated breast tumor stem or progenitor cells.