Mechanistic significance of a novel molecular target in the FOXO signaling pathwa

描述（由申请人提供）：三阴性乳腺癌（TNBC）是一种侵袭性乳腺癌，常见于非裔美国妇女和BRCA1突变携带者。在标准的细胞毒性化疗后，TNBC肿瘤经常复发并远处转移。这项小型研究应用的总体研究目标是阐明乳腺癌化疗敏感性的新机制。虽然一些凋亡分子确实增强了化疗药物的细胞毒性作用，但迄今为止，这些分子都不是晚期乳腺癌的临床强有力的靶点。为此，我们已经证明含有细胞死亡诱导剂的bhd -3样基序是侵袭性乳腺癌的一个强有力的预后因素。近年来，盲蛋白的表达已被证明可以抑制乳腺癌细胞的生长和转移。此外，与1级和2级乳腺癌相比，某些3级乳腺癌的blad mRNA表达显著降低，这表明blad的转录调控可能在乳腺癌进展中发挥作用。尽管Forkhead boxO （FOXO）转录调控子亚家族的成员与乳腺癌的发病和预后有关，但它们在乳腺癌中的作用机制在很大程度上是未知的。因此，解释和靶向这些机制的方法可以为安全有效地治疗乳腺癌提供重要线索。在初步研究中，blad可能是FOXO3a的一种效应因子，表达blad cDNA纳米疗法可增加乳腺癌细胞的化疗敏感性。此外，microrna miR-21、miR-155和miR-34a可能是FOXO/ blind信号通路的组成部分。具体的研究目的是：1)利用DNA亲和纯化和质谱技术，以及ChIP-Seq策略，揭示新的foxo - blind信号通路及其在乳腺癌细胞中介导的化学敏感性。2)探讨blad和microrna在TNBC细胞化学致敏中的综合作用。这项研究的成功结果将为未来全面分析foxo - blind信号通路的研究提供基础，这可能解释某些乳腺癌化疗失败的原因。这项工作也将建立第一个功能之间的联系

DESCRIPTION (provided by applicant): The triple negative breast cancer (TNBC) is an aggressive form of breast cancer frequently seen in African American women and BRCA1 mutation carriers. The TNBC tumors often relapse with distant metastases following standard cytotoxic chemotherapy. The overarching research objective of this small research application is to elucidate a new mechanism of chemosensitivity of breast cancer. While some apoptotic molecules do enhance cytotoxic effects of chemotherapeutic drugs, to date none of these molecules is a clinically robust target in advanced breast cancer. To this end, we have demonstrated that BLID, BH-3 Like motif containing Inducer of cell Death, is a strong prognostic factor in invasive breast cancer. Recently, BLID expression has been shown to inhibit breast cancer cell growth and metastasis. In addition, BLID mRNA expression is significantly reduced in certain grade 3 relative to grade 1 and grade 2 breast cancers, suggesting a potential role of transcriptional regulation of BLID in breast cancer progression. Despite the fact that members of the Forkhead boxO (FOXO) subfamily of transcriptional regulators have been linked with breast pathogenesis and prognosis, their mechanisms of action in breast cancer are largely unknown. Therefore, approaches that explain and target such mechanisms could offer important clues to safe and effective ways of managing breast cancer. In preliminary studies, BLID seems to be a likely effector of FOXO3a, and expression of BLID cDNA nanotherapeutic increases chemosensitivity in breast cancer cells. Furthermore, microRNAs miR-21, miR-155 and miR-34a may be components of the FOXO/BLID signaling pathway. The specific research aims are: 1) To demonstrate a novel FOXO-BLID signaling pathway and BLID-mediated chemosensitivity in breast cancer cells using DNA affinity purification and mass spectrometry, and the ChIP-Seq strategy. 2) To examine the integrative roles of BLID and microRNAs in chemosensitization of TNBC cells. Successful outcomes of this research will provide the basis for future studies of a comprehensive analysis of the FOXO-BLID signaling pathway that may explain why certain breast cancers fail chemotherapies. This work will also establish the first functional link between BLID and three prominent microRNAs, and may lead to a prospective validation of the microRNA module(s) in clinical TNBC specimens. Building on this project, a new systems biology approach involving FOXO/BLID-centric gene networks and circulating microRNAs could be developed. This information will be unique and significant since very little is known about the systems biology of TNBC cell death and drug sensitivity or resistance.