Transfer RNAs as Biomarkers and Regulators in Breast Cancer

描述（由申请人提供）：乳腺癌研究的一个主要挑战是识别用于早期诊断、预测肿瘤侵袭性和确定最合适疗程的准确标志物。找到这些标志物的一种方法是开发一种可以区分不同癌症类型的分子谱。该提案将研究转移RNA（tRNA）作为乳腺癌生物标志物的潜力，以及它们在调节乳腺癌细胞的发展和进展中的作用。转移RNA以其在翻译中的作用而闻名，在翻译中，它们读取mRNA密码子并将适当的氨基酸带到新生的多肽链中。人类基因组序列中一个意想不到的发现是编码tRNA的基因序列的巨大多样性，远远超出了翻译所需的范围。人类tRNA序列的巨大多样性表明癌细胞可能产生独特的tRNA表达模式，这可能用作癌症类型或进展的生物标志物。独特的tRNA微阵列技术将被应用于分析转化和正常乳腺细胞系中的tRNA表达水平。初步结果表明，tRNA水平将随着致癌转化而变化，并可能表现出基于不同信号通路上调的选择性模式。确立tRNA作为生物标志物的潜力将为检测乳腺肿瘤的类型和阶段开辟新的途径。此外，某些tRNA的过表达可能会驱动致癌转化。在乳腺癌细胞系中强烈上调的引发剂甲硫氨酸tRNA和其他tRNA将在正常乳腺细胞中过表达，以确定它们是否可以驱动细胞增殖和转化。这一机制的验证将确立调节tRNA表达作为控制癌细胞发展和进展的新手段。这些tRNA和参与其调节的基因可能成为一类新的癌症药物的靶点。在世界范围内，乳腺癌是第二种最常见的癌症。乳腺癌研究中的一个主要挑战是确定早期诊断的准确标记物，预测肿瘤的侵袭性，并确定最合适的治疗方案。这项工作将评估转移RNA作为乳腺癌生物标志物的潜力及其在乳腺癌细胞发展中的作用。

DESCRIPTION (provided by applicant): A major challenge in breast cancer research is to identify accurate markers for early diagnosis, prediction of tumor aggressivity, and determination of the most appropriate course of treatment. One approach to finding such markers is to develop a molecular profile that can distinguish between different cancer types. This proposal will examine the potential of transfer RNAs (tRNAs) to serve as breast cancer biomarkers, as well as their role in regulating the development and progression of breast cancer cells. Transfer RNAs are best known for their role in translation, where they read mRNA codons and bring the appropriate amino acid to the nascent polypeptide chain. An unexpected finding from the human genome sequence is the large diversity of gene sequences coding for tRNAs, well beyond that needed for translation. This large diversity in sequence of human tRNAs suggests that cancer cells may generate unique patterns of tRNA expression, which could be useful as biomarkers for cancer types or progression. Unique tRNA microarray technology will be applied to profile tRNA expression levels in transformed and normal breast cell lines. Preliminary results indicate tRNA levels will change with oncogenic transformation, and may exhibit selective patterns based on upregulation of distinct signaling pathways. Establishing the potential of tRNAs as biomarkers will open up a new avenue for detecting the type and stage of breast tumors. In addition, overexpression of certain tRNAs may drive oncogenic transformation. Initiator methionine tRNA and other tRNAs strongly upregulated in breast cancer cell lines will be overexpressed in normal breast cells to determine whether they can drive cell proliferation and transformation. Validation of this mechanism will establish modulation of tRNA expression as a novel means for controlling the development and progression of cancer cells. Such tRNAs and the genes involved in their regulation could be targets for a new class of cancer drugs. Worldwide, breast cancer is the second most common type of cancer. A major challenge in breast cancer research is to identify accurate markers for early diagnosis, prediction of tumor aggressivity, and determination of the most appropriate course of treatment. This work will evaluate the potential of transfer RNAs to serve as biomarkers for breast cancer and their role in the development of breast cancer cells.