Role of ITAM repeats in virus-induced breast cancer

描述（由申请人提供）：在动物模型中对逆转录病毒诱导的癌症进行的研究已经鉴定了涉及细胞生长和调节的几乎所有方面的大量基因。已经确定MMTV是一种在小鼠中引起乳腺癌的鼠逆转录病毒，它在肿瘤细胞中整合到许多细胞癌基因旁边，从而诱导它们的不适当表达。然而，我们最近发现，异位表达的MMTV包膜蛋白在正常的乳腺上皮细胞的结果，在其表型转化和免疫酪氨酸为基础的激活基序（ITAM）在这种蛋白质是至关重要的，这种活动。ITAM通常存在于造血细胞中表达的受体中，并且受到细胞类型特异性调节剂如B细胞特异性分子CD22的负调节。我们推测，不受控制的信号转导的包膜蛋白在上皮细胞，缺乏这样的调制器，是一个早期的步骤，在MMTV的转化过程。ITAM介导的信号传导可能是体内病毒感染所必需的，并且诱导失调的细胞生长可能是这种需求的副产物。由于ITAM在病毒和细胞蛋白中均存在，因此此类信号分子的不适当表达代表了一种新的转化机制。因此，本提案的总体目标是确定MMTV包膜蛋白在乳腺感染和肿瘤发生中的体内作用，从而确定含ITAM的蛋白是否在乳腺癌和其他非造血系统癌症中发挥作用。这些研究对于开发乳腺癌和其他癌症的新治疗模式具有潜在的重要性，特别是那些与编码激活ITAM介导的信号传导的蛋白质的病毒相关的癌症。

DESCRIPTION (provided by applicant): The study of retrovirus-induced cancers in animal models has resulted in the identification of scores of genes involved in virtually all aspects of cell growth and regulation. It is well-established that MMTV, a murine retrovirus that causes breast cancer in mice, integrates next to a number of cellular oncogenes in tumor cells, thereby inducing their inappropriate expression. However, we have recently found that ectopic expression of the MMTV envelope protein in normal mammary epithelial cells results in their phenotypic transformation and that an immuno-tyrosine based activation motif (ITAM) in this protein is critical to this activity. ITAMs are commonly found in receptors expressed in hematopoietic cells and are negatively regulated by cell-type specific modulators such as the B-cell specific molecule CD22. We speculate that uncontrolled signaling by the envelope protein in an epithelial cell, which lacks such modulators, is an early step in the MMTV transformation process. ITAM-mediated signaling may be required for virus infection in vivo and the induction of dysregulated cell growth may be a by-product of this requirement. Because ITAMs are found both in viral and cellular proteins, inappropriate expression of such signaling molecules represents a novel mechanism of transformation. Thus, the overall goals of this proposal are to determine the in vivo role of the MMTV envelope protein in mammary gland infection and tumorigenesis and thereby to determine whether ITAM-containing proteins play a role in breast and other non-hematopoietic cancers. These studies are of potential importance in developing new treatment paradigms for breast and other cancers, especially those associated with viruses that encode proteins that activate ITAM-mediated signaling.