Molecular mechanism of ID1 function in advanced breast cancer

ID1在晚期乳腺癌中发挥作用的分子机制

• 批准号: 8518047
• 负责人: Meiyun Fan
• 金额: $ 22.18万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8518047
• 关键词: Adopted; Advanced Malignant Neoplasm; American; BHLH Protein; Bioinformatics; Boxing; Breast Cancer Cell; Breast Cancer Treatment; Cells; Cues; DNA Binding; Databases; Development; Diagnosis; Differentiation Inhibitor; Disease; Drug resistance; E-Box Elements; ESR1 gene; Ectopic Expression; Environment; Estrogen Antagonists; Estrogen Receptor Modulators; Estrogen Receptors; Estrogens; Exposure to; Family; Foundations; Fulvestrant; Gene Expression; Gene Expression Profile; Gene Targeting; Genes; Genetic Transcription; Genome; Genomics; Growth; Health; Helix-Loop-Helix Motifs; Hormones; Human; Lead; Maintenance; Mammary Neoplasms; Mediating; Meta-Analysis; MicroRNAs; Molecular; Neoplasm Metastasis; Pattern; Phenotype; Play; Process; Promoter Regions; Publishing; Regulation; Reporting; Resistance; Role; Specific qualifier value; Staging; Structure; Testing; Therapeutic; Time; Transcriptional Regulation; Tumor Tissue; Woman; cell growth; clinically relevant; gain of function; genome-wide analysis; hormone sensitivity; human data; insight; loss of function; malignant breast neoplasm; mortality; neoplastic cell; promoter; protein protein interaction; transcription factor; tumor; tumor progression; tumorigenic

DESCRIPTION (provided by applicant): In 2008 more than 200,000 American women will be diagnosed with breast cancer and many will be treated with antiestrogens. Unfortunately, many breast tumors initially respond to antiestrogens will become unresponsive over time, leading to metastasis and mortality. The molecular mechanisms of breast cancer progression are largely unknown, which hinders the development of targeted therapies for advanced cancer. Our recent studies showed that ID1, an inhibitor of differentiation, played a role in promoting breast cancer cells to adopt an aggressive, hormone-independent phenotype, resulting in antiestrogen resistance. The significance of our finding is underscored by recent reports that ID1 is highly expressed in poorly differentiated, metastatic tumors. The primary function of ID1 is to inhibit DNA binding of a family of transcription factors that contain a basic helix-loop-helix (bHLH) domain. To identify the potential bHLH transcription factor that is regulated by ID1 in breast cancer cells, we performed a comprehensive bioinformatic analysis of published gene expression data of human breast tumors. Meta-analysis revealed that the expression of BHLHB2, a bHLH transcription factor and putative target of ID1, is strongly associated with hormone-dependent breast tumors, and BHLHB2-coexpressed genes significantly overlap with genes coexpressed with ESR1, FOXA1 and GATA3, the key transcription factors that specify the hormone-dependent phenotype of breast cancer. In addition, we found that E-box motif, the cis-regulatory sequence recognized by BHLHB2, was overrepresented in ESR1 direct target genes. We hypothesize that BHLHB2 is an integral component of a transcription regulatory network that dictates the hormone-dependent phenotype of breast cancer, and ID1 facilitates tumor cells to acquire a poorly differentiated phenotype by inhibiting BHLHB2 function. We will test this hypothesis in the following three specific aims by conducting a systematic and detailed study on the function and regulation of BHLHB2 in breast cancer cells. Specifically, we will: 1) investigate the role of BHLHB2 in maintaining hormone-dependent phenotype and its regulation by ID1 by examining the consequences of gain- or loss-of- function of BHLHB2 and ID1 in human breast cancer cells; 2) identify and characterize genes regulated by BHLHB2 and ID1 using high-throughput genome-wide analysis of gene expression and BHLHB2 DNA binding; and 3) investigate the regulation and function of fulvestrant resistance-related miRNAs, with emphasis on the cross-regulation between the fulvestrant resistant-relate miRNA and core transcription factors of hormone- dependent breast cancer cells.

描述（由申请人提供）：2008年，超过20万名美国妇女将被诊断患有乳腺癌，许多人将接受抗雌激素治疗。不幸的是，许多乳腺肿瘤最初对抗雌激素有反应，随着时间的推移会变得无反应，导致转移和死亡。乳腺癌进展的分子机制在很大程度上尚不清楚，这阻碍了晚期癌症靶向治疗的开发。我们最近的研究表明，ID 1，一种分化抑制剂，在促进乳腺癌细胞采取一种侵略性的，非依赖性的表型，导致抗雌激素抵抗中发挥作用。最近的报道强调了我们发现的重要性，即ID 1在低分化的转移性肿瘤中高度表达。ID 1的主要功能是抑制含有碱性螺旋-环-螺旋（bHLH）结构域的转录因子家族的DNA结合。为了确定乳腺癌细胞中受ID 1调控的潜在bHLH转录因子，我们对已发表的人类乳腺肿瘤基因表达数据进行了全面的生物信息学分析。荟萃分析显示，BHLHB 2，一个bHLH转录因子和ID 1的假定目标，表达与乳腺癌依赖性乳腺肿瘤密切相关，BHLHB 2共表达基因与ESR 1，FOXA 1和GATA 3共表达基因显著重叠，ESR 1，FOXA 1和GATA 3是乳腺癌依赖性表型的关键转录因子。此外，我们发现，E-box基序，BHLHB 2识别的顺式调控序列，在ESR 1的直接靶基因中的过度表达。我们假设BHLHB 2是一个转录调控网络的一个组成部分，决定了乳腺癌的乳腺癌依赖表型，ID 1通过抑制BHLHB 2功能促进肿瘤细胞获得低分化表型。我们将通过对BHLHB 2在乳腺癌细胞中的功能和调节进行系统和详细的研究，在以下三个具体目标中验证这一假设。具体而言，我们将：1）通过检查BHLHB 2和ID 1在人乳腺癌细胞中获得或丧失功能的后果来研究BHLHB 2在维持乳腺癌依赖性表型中的作用及其由ID 1的调节; 2）使用基因表达和BHLHB 2 DNA结合的高通量全基因组分析来鉴定和表征由BHLHB 2和ID 1调节的基因; 3）研究氟维司群耐药相关miRNA的调控和功能，重点研究氟维司群耐药相关miRNA与激素依赖性乳腺癌细胞核心转录因子之间的交叉调控。

项目成果

Systematic analysis of metastasis-associated genes identifies miR-17-5p as a metastatic suppressor of basal-like breast cancer.

• DOI: 10.1007/s10549-014-3040-5
• 发表时间: 2014-08
• 期刊: BREAST CANCER RESEARCH AND TREATMENT
• 影响因子: 3.8
• 作者: Fan, Meiyun;Sethuraman, Aarti;Brown, Martin;Sun, Wenlin;Pfeffer, Lawrence M.
• 通讯作者: Pfeffer, Lawrence M.

MicroRNA-18a inhibits hypoxia-inducible factor 1α activity and lung metastasis in basal breast cancers.

• DOI: 10.1186/bcr3693
• 发表时间: 2014-07-28
• 期刊: Breast cancer research : BCR
• 作者: Krutilina R;Sun W;Sethuraman A;Brown M;Seagroves TN;Pfeffer LM;Ignatova T;Fan M
• 通讯作者: Fan M

Induction of miRNA-181a by genotoxic treatments promotes chemotherapeutic resistance and metastasis in breast cancer.

基因毒性治疗诱导 miRNA-181a 促进乳腺癌化疗耐药和转移

• DOI: 10.1038/onc.2015.189
• 发表时间: 2016-03-10
• 期刊: Oncogene
• 影响因子: 8
• 作者: Niu J;Xue A;Chi Y;Xue J;Wang W;Zhao Z;Fan M;Yang CH;Shao ZM;Pfeffer LM;Wu J;Wu ZH
• 通讯作者: Wu ZH