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：
8323007
负责人：
VICTORIA L. SEEWALDT
金额：
$ 4.31万
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/8323007
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.

描述（申请人提供）：三阴性乳腺癌[ER/PR-/-、HER2/neu wt、EGFR+]常见于年轻女性，预后不良。虽然并非所有三阴性乳腺癌都是致命的，但绝经前非裔美国女性的 5 年死亡率为三阴性乳腺癌的 86%。由于许多三阴性乳腺癌在诊断时具有化疗耐药性，因此非常需要早期检测。在这里，我们的目标是研究一种有望早期检测三阴性乳腺癌的新型信号通路。TASK3 是一种 pH 敏感的钾通道蛋白，可调节线粒体膜电位 m)。 TASK3的过度表达增加m，从而促进细胞凋亡抵抗和缺氧耐受。在初步数据中，我们表明 TASK3 在 1) 化疗耐药的转移性三阴性乳腺癌和 2) 高危非裔美国女性的癌前乳腺疾病中过度表达。 KCNK9（TASK3 基因）受印记调节：印记的丧失可预测三阴性乳腺癌的化疗耐药性和随后的转移：编码 TASK3 蛋白的基因 KCNK9 受甲基化印记调节。印记是一种正常的调控过程，其中基因的一个副本失活，导致单等位基因表达。正常印记的丧失会导致功能性二倍体状态和靶基因的过度表达。 KCNK9基因的一份拷贝通常被印记，使得KCNK9单倍体处于正常功能状态（一份基因拷贝表达，一份不表达）。在初步数据中，我们在 KCNK9 启动子中发现了一个差异甲基化区域 (DMR)，该区域在正常乳腺上皮细胞中印迹，但在原发性化疗耐药的三阴性乳腺癌中不印迹。 DMR 印记的丧失预示着 TASK3 过度表达、化疗耐药和随后的转移。假设：KCNK9 DMR 甲基化印记的缺失和缺氧协同促进三阴性乳腺癌中 TASK3 的过表达和转移。目标 1 将测试缺氧是否会在缺乏 KCNK9 DMR 印记的三阴性乳腺癌中转录激活 TASK3。我们将对常氧和缺氧条件下的 KCNK9 HRE 活性、TASK3 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。目标 2 将测试正常 KCNK9 DMR 印记的丧失是否会促进三阴性乳腺癌的发生、进展和转移。意义：成功完成该提案的目标将提高我们识别生物侵袭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女性中死亡率很高。我们建立的高风险队列将使我们能够快速测试 KCNK9 DMR 印记的丧失是否会促进化疗耐药的转移性三阴性乳腺癌。