KCNK9 Imprinting in Breast Cancer Progression and Metastasis

KCNK9 印记在乳腺癌进展和转移中的作用

基本信息

批准号：
8033963
负责人：
VICTORIA L. SEEWALDT
金额：
$ 32.58万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-06 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8033963
关键词：
African American Aggressive behavior Apoptosis Atypia Breast Breast Cancer Cell Breast Diseases Caucasians Caucasoid Race Chemotherapy-Oncologic Procedure Code CpG Islands Cytology Data Diagnosis Diet Diploidy Disease ERBB2 gene Early Diagnosis Environmental Exposure Epidermal Growth Factor Receptor Epigenetic Process Epithelial Cells Estrogen receptor negative Fine needle aspiration biopsy Gene Expression Gene Targeting Genes Haploidy Hemoglobin Hypoxia In Vitro Lesion Link Mammary gland Membrane Potentials Metastatic Neoplasm to the Breast Methylation Molecular Mono-S Neoplasm Metastasis Pathway interactions Potassium Channel Premalignant Premenopause Prevention strategy Process Proteins Regulation Reporting Research Technics Resistance Response Elements Signal Pathway Testing Tissue Banking Tissue Banks Woman cancer initiation cancer risk caucasian American chemotherapy cohort high risk imprint improved in vivo malignant breast neoplasm mitochondrial membrane mortality novel outcome forecast overexpression promoter prospective triple-negative invasive breast carcinoma tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Triple-negative breast cancers [ER/PR-/-, HER2/neu wt, EGFR+] frequently occur in young women and carry a poor prognosis. While not all triple-negative breast cancers are lethal, triple-negative breast cancers have 86% 5-year mortality in pre-menopausal African American women. Since many triple-negative breast cancers are chemotherapy-resistant at diagnosis, there is a great need for early detection. Here we aim to investigate a novel signaling pathway that holds promise for early detection of triple-negative breast cancer.TASK3 is a pH sensitive potassium channel protein that regulates mitochondrial membrane potential m). Overexpression of TASK3 increases m, and thereby promotes apoptosis resistance and tolerance of hypoxia. In Preliminary Data, we show that TASK3 is overexpressed in 1) chemotherapy-resistant metastatic triple-negative breast cancers and 2) premalignant breast disease in high-risk African American women. KCNK9 (TASK3 gene) is regulated by imprinting: loss of imprinting predicts chemotherapy resistance and subsequent metastasis of triple-negative breast cancer: The gene coding for the TASK3 protein, KCNK9, is regulated by methylation imprinting. Imprinting is a normal regulatory process where one copy of the gene is inactivated resulting in mono-allelic gene expression. Loss of normal imprinting results in a functional diploid state and overexpression of the target gene. One copy of the KCNK9 gene is normally imprinted, making the normal functional state of KCNK9 haploid (one gene copy expressed, one copy not expressed). In Preliminary Data, we identified a differentially methylated region (DMR) in the KCNK9 promoter that was imprinted in normal mammary epithelial cells but not in primary chemotherapy-resistant triple-negative breast cancers. Loss of DMR imprinting predicted TASK3 overexpression, chemotherapy-resistance, and subsequent metastasis. Hypothesis: Loss of methylation imprinting of KCNK9 DMR and hypoxia synergistically promote TASK3 overexpression and metastasis in triple-negative breast cancer. Aim 1 will test whether hypoxia transcriptionally activates TASK3 in triple-negative breast cancers that lack imprinting of the KCNK9 DMR. We will perform in vivo multi-parametric analysis of KCNK9 HRE activity, TASK3 expression, tumor growth and metastasis, and hemoglobin saturation in normoxic and hypoxic conditions. Aim 2 will test whether loss of normal KCNK9 DMR imprinting promote initiation, progression, and metastasis of triple-negative breast cancer. Significance: Successful completion of the aims of this proposal will improve our ability to identify biologically aggressive metastatic triple-negative breast cancer. Triple-negative breast cancers have a high mortality in premenopausal African American women. Our established high-risk cohort will allow us to rapidly test whether loss of KCNK9 DMR imprinting promotes chemotherapy-resistant metastatic triple- negative breast cancers. PUBLIC HEALTH RELEVANCE: The molecular origins of estrogen receptor-negative (ER-) breast cancers in African American and Caucasian women are poorly understood. Importantly, we do not understand whether the molecular pathways that underlie the aggressive behavior of ER(-) breast cancers can be detected in premalignant lesions. This information is crucial for developing successful early detection and targeted-prevention strategies. Here we take trans-disciplinary approach to investigate the epigenetic origins of ER(-) breast cancer in our Duke breast cancer tissue bank and world-class prospective cohort of high-risk pre- menopausal Caucasian and African American women.. PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Format Page

描述（由申请人提供）：三阴性乳腺癌[ER/PR - / - ，HER2/NEU WT，EGFR+]经常出现在年轻女性中，预后不佳。虽然并非所有三阴性乳腺癌都是致命的，但三阴性乳腺癌在绝经前的非洲裔美国妇女中具有86％的5年死亡率。由于许多三阴性乳腺癌在诊断时具有耐化疗，因此非常需要尽早检测。在这里，我们旨在研究一种新的信号通路，该通路有望早期检测三阴性乳腺癌。Task3是一种调节线粒体膜电位m的pH敏感钾通道蛋白。任务3的过表达增加了M，从而促进了缺氧的凋亡耐药性和耐受性。在初步数据中，我们显示任务3在1）耐化疗转移性三阴性乳腺癌和2）高危非裔美国妇女中的乳房疾病前乳房疾病过表达。 KCNK9（task3基因）受印迹的调节：烙印的丧失预测化疗的耐药性和随后三阴性乳腺癌的转移：编码任务3蛋白KCNK9的基因受甲基化印记调节。印迹是一种正常的调节过程，其中一个基因的副本被灭活，导致单相关基因表达。正常印迹的丧失导致功能性二倍体状态和目标基因的过表达。通常将KCNK9基因的一个副本置于印记，从而使KCNK9单倍体的正常功能状态（表示一个基因副本，一个未表达的副本）。在初步数据中，我们在KCNK9启动子中鉴定了差异甲基化区域（DMR），该区域被印在正常乳腺上皮细胞中，但在原发性化学疗法耐药的三阴性乳腺癌中却没有。 DMR印记的丧失预测任务3过表达，化学疗法抗性和随后的转移。假设：KCNK9 DMR和缺氧的甲基化损失协同促进任务3三阴性乳腺癌中的过表达和转移。 AIM 1将测试缺氧是否在缺乏KCNK9 DMR印迹的三阴性乳腺癌中激活Tast3。我们将对在常氧和低氧条件下的KCNK9 HRE活性，Tast3表达，肿瘤生长和转移以及血红蛋白饱和度进行体内多参数分析。 AIM 2将测试损失正常的KCNK9 DMR烙印是否会促进三阴性乳腺癌的开始，进展和转移。意义：成功完成该提案的目标将提高我们鉴定生物学上侵略性转移性三阴性乳腺癌的能力。三阴性乳腺癌在绝经前非裔美国妇女中死亡。我们已建立的高风险队列将使我们能够快速测试KCNK9 DMR烙印是否促进了耐化学疗法的转移性三重乳腺癌。公共卫生相关性：非洲裔美国人和高加索妇女中雌激素受体阴性（ER-）乳腺癌的分子起源知之甚少。重要的是，我们不了解是否可以在预临床病变中检测到ER（ - ）乳腺癌的侵略性行为的分子途径。该信息对于制定成功的早期检测和针对性预防策略至关重要。在这里，我们采用跨学科方法来研究我们杜克乳腺癌组织库中ER（ - ）乳腺癌的表观遗传起源，以及世界一流的前瞻性高风险前pres-绝经前白种人和非裔美国人女性。