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确定准确的早期诊断标志物，预测肿瘤侵袭性，并确定最合适的治疗方案。寻找这类标记物的一种方法是开发一种能够区分不同癌症类型的分子图谱。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育和进展中的作用。转移rna最为人所知的是它们在翻译中的作用，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。人类基因组序列的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多样性。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，这可能是癌症类型或进展的有用生物标志物。独特的tRNA微阵列技术将应用于转化和正常乳腺细胞系中tRNA表达水平的分析。初步结果表明，tRNA水平会随着致癌转化而改变，并可能表现出基于不同信号通路上调的选择性模式。确定trna作为生物标志物的潜力将为检测乳腺肿瘤的类型和分期开辟新的途径。此外，某些trna的过表达可能会驱动致癌转化。引发剂蛋氨酸tRNA等在乳腺癌细胞系中被强烈上调的tRNA会在正常乳腺细胞中过表达，从而决定其是否能驱动细胞增殖转化。这一机制的验证将建立tRNA表达的调节作为控制癌细胞发展和进展的新手段。这类trna及其调控基因可能成为一类新型抗癌药物的靶标。在世界范围内，乳腺癌是第二常见的癌症类型。乳腺癌研究的一个主要挑战是确定准确的早期诊断标志物，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.