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Role of Estrogen and Iron in Breast Cancer

雌激素和铁在乳腺癌中的作用

基本信息

批准号：
7463749
负责人：
XI HUANG
金额：
$ 20.33万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-05 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7463749
关键词：
17p 8-Oxo-2&apos -Deoxyguanosine Antigens Breast Cancer Risk Factor Cancer Etiology Cancer cell line Cell Line Cells Characteristics Condition DNA Deoxyguanosine Development Epithelial Estradiol Estrogen Receptors Estrogens Fatty acid glycerol esters Female Gene Mutation Genes Growth Health Benefit Hemochromatosis Hemorrhage Implant Incidence Iron Mammary Gland Parenchyma Mammary Neoplasms Mammary gland Measures Mediating Menopause Methods Modeling Mouse Strains Mus Mutation Ovariectomy Play Postmenopause Premenopause Progesterone Receptors Proteins Puberty RNA Rate Research Risk Factors Role Serum iron level result Small Interfering RNA Testing Transfer RNA Transferrin Receptor Transgenic Organisms Tumor Volume Tumorigenicity Week Wild Type Mouse Woman Women&apos s Health cancer cell implantation malignant breast neoplasm mouse model mutant neoplastic receptor tumor tumor growth uptake young adult

项目摘要

DESCRIPTION (provided by applicant): Breast cancer (BC) incidence rates are much higher in post- than pre-menopausal women. Estrogen is a well-known risk factor for BC development. Yet, total estrogen levels are lower in post- than pre-menopausal women. This apparent discrepancy calls for new research to better understand BC etiology and mechanisms. In the present study, we hypothesize that an accumulation of high iron levels due to menopause is one of the pre-neoplastic changes in post-menopausal women, and in the presence of high local estrogen in the breast tissue, both iron and estrogen greatly promote breast tumor growth and oxidative damage. We will test this hypothesis using an ovariectomized (OVX) transgenic iron-loaded mouse model carrying hemochromatosis (HFE) gene mutation. This model has a decreased estrogen level because of the OVX, but an increased iron level due to the HFE gene mutation, thus mimicking post-menopausal conditions. In Aim1, we will assess the role of estrogen in mammary epithelial proliferation and spontaneous tumor formation in wild-type and iron loaded HFE+/- mice. Female wild-type C57BL6 mice and HFE+/- mice will undergo OVX. After implantation of 17beta-estradiol (E2), Ki-67, a proliferation-specific antigen, and spontaneous tumor incidence of the iron-loaded mutant and wild-type mice will be compared. In Aim 2, we will assess whether E2 induces a higher tumor take and growth of mammary cancer in HFE+/- mice than in wild-type mice. MXT+ mammary cancer cells will be inoculated into the mammary fat pads of wild-type and HFE+/- mice. Mammary cancer tumorigenicity and tumor latency as well as tumor volume will be measured. Levels of oxidative DNA and protein in breast tissues will be determined and compared. In Aim 3, we will determine whether E2-mediated tumor growth is iron-dependent. The MXT+ cell line will be transfected with small interfering RNA (siRNA) of transferring receptor. Mammary cancer will be measured and compared between the siRNA transfectants and the parental cells. We expect to show that iron plays an important role in estrogen-dependent BC and this new direction of research may greatly benefit the health of female baby- boomers.

描述（由申请人提供）：绝经后女性的乳腺癌（BC）发病率远高于绝经前女性。雌激素是BC发展的一个众所周知的风险因素。然而，绝经后妇女的总雌激素水平低于绝经前妇女。这种明显的差异需要新的研究来更好地了解BC的病因和机制。在本研究中，我们假设，由于绝经期的高铁水平的积累是绝经后妇女的肿瘤前的变化之一，并在高的局部雌激素在乳腺组织中的存在下，铁和雌激素大大促进乳腺肿瘤的生长和氧化损伤。我们将使用携带血色素沉着症（HFE）基因突变的卵巢切除（OVX）转基因铁负载小鼠模型来验证这一假设。该模型由于OVX而具有降低的雌激素水平，但是由于HFE基因突变而具有增加的铁水平，从而模拟绝经后状况。在Aim 1中，我们将评估雌激素在野生型和铁负载HFE+/-小鼠中乳腺上皮增殖和自发性肿瘤形成中的作用。雌性野生型C57 BL 6小鼠和HFE+/-小鼠将经历OVX。植入17 β-雌二醇（E2）后，将比较载铁突变体和野生型小鼠的增殖特异性抗原Ki-67和自发肿瘤发生率。在目标2中，我们将评估E2是否在HFE+/-小鼠中比在野生型小鼠中诱导更高的肿瘤摄取和乳腺癌生长。将MXT+乳腺癌细胞接种到野生型和HFE+/-小鼠的乳腺脂肪垫中。将测量乳腺癌致瘤性和肿瘤潜伏期以及肿瘤体积。将测定并比较乳腺组织中氧化DNA和蛋白质的水平。在目标3中，我们将确定E2介导的肿瘤生长是否是铁依赖性的。将用转移受体的小干扰RNA（siRNA）转染MXT+细胞系。将测量乳腺癌并在SiRNA转染子和亲代细胞之间进行比较。我们期望表明铁在雌激素依赖性BC中起着重要作用，这一新的研究方向可能会极大地有益于女性婴儿潮一代的健康。