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Steroid Hormones Regulate Ovarian Cancer Progression and Metastasis

类固醇激素调节卵巢癌的进展和转移

基本信息

批准号：
8923209
负责人：
JoAnne Stewart Richards
金额：
$ 33.66万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-08 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8923209
关键词：
Address Age Cancer Cell Growth Cancer cell line Cause of Death Cells Cessation of life Clinical Data Development Diagnostic Disease Environment Epidemiology Epithelial Cells Epithelial ovarian cancer Estradiol Estradiol Receptors Estrogen Receptors Estrogens Exhibits Gene Targeting Genes Genetic Genomic Instability Goals Growth Health Hormone replacement therapy Hormones Human Human Cell Line In Situ Incidence Intercept Life Link Malignant Neoplasms Malignant neoplasm of ovary Mediating Menopausal Symptom Mesentery Metastatic Neoplasm to the Peritoneum Modeling Molecular Mus Mutant Strains Mice Mutation Neoplasm Metastasis Omentum Oncogenic Operative Surgical Procedures Oral Contraceptives Ovarian Ovarian Surface Epithelial-Stromal Tumor Pathway interactions Peritoneal Progesterone Progesterone Receptors Progestins Recurrence Repressor Proteins Risk Serous Cystadenocarcinoma Site Staging Steroids Surface TP53 gene Tamoxifen Testing Time Transgenes Transgenic Mice Wild Type Mouse Woman Women&apos s Health base cancer cell cancer risk cell transformation clinically relevant functional status in vivo insight mouse model mutant mutant mouse model neoplastic cell novel outcome forecast ovarian neoplasm receptor response steroid hormone tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Understanding the actions and interactions of ovarian steroids (estradiol and progesterone) and the tumor repressor protein (TRP53, TP53) becomes of utmost clinical relevance when epithelial cells undergo oncogenic transformation to form cancers. Ovarian (epithelial) cancer is of paramount importance because this disease is the fifth most lethal cause of death in women and, with more than 14,000 deaths annually, remains an ominous threat to women's health. Clinical and epidemiological data show a strong link between ovarian steroids and ovarian cancer; ~90% of ovarian cancers harbor mutations in TP53. Unfortunately, little is known about the molecular mechanisms by which TP53 status and steroids impact ovarian cancer tumor progression and metastasis. We have generated unique mouse models that will allow us to define the actions of estradiol on ovarian epithelial cell cancer in vivo. Based on provocative observations in these mice, we hypothesize that increased expression of ER�?and estrogen-induced genes mediate ovarian cancer tumor growth and metastasis in ovarian cancers lacking functional TRP53 (tumor repressor protein 53 or p53) or expressing mutant TRP53. These powerful mouse models combined with human ovarian cancer cell lines will allow us to determine for the first time: 1) how steroids control ovarian cancer cell progression and metastasis in vivo; 2) which specific genes are targets of estrogen in the transformed cells in vivo and 3) if intercepting these pathways by progesterone or estrogen receptor antagonists blocks metastasis or tumor growth and 4) how estradiol alters the metastatic sites. To address these goals we propose the following specific aims. Specific Aim 1: Determine the molecular mechanisms by which TRP53 and estradiol impact ovarian tumor progression and metastasis in vivo. Specific Aim 2: Determine the impact of mutant TRP53(R172H) on hormone-regulated ovarian tumor progression and metastasis in vivo. Specific Aim 3: Determine if metastatic tumor growth involves TRP53 status and steroid action in peritoneal cells.

描述（由申请人提供）：当上皮细胞发生致癌转化形成癌症时，了解卵巢类固醇（雌二醇和孕酮）和肿瘤抑制蛋白（TRP 53，TP 53）的作用和相互作用具有最大的临床意义。卵巢（上皮）癌至关重要，因为这种疾病是妇女第五大致死原因，每年有14 000多人死亡，仍然是对妇女健康的不祥威胁。临床和流行病学数据显示，卵巢类固醇与卵巢癌之间存在密切联系;约90%的卵巢癌在TP 53中存在突变。不幸的是，关于TP 53状态和类固醇影响卵巢癌肿瘤进展和转移的分子机制知之甚少。我们已经建立了独特的小鼠模型，这将使我们能够确定雌二醇对卵巢上皮细胞癌的作用。基于对这些小鼠的挑衅性观察，我们假设ER β表达的增加？在缺乏功能性TRP 53（肿瘤抑制蛋白53或p53）或表达突变型TRP 53的卵巢癌中，雌激素诱导的基因介导卵巢癌肿瘤生长和转移。这些强大的小鼠模型与人卵巢癌细胞系相结合将使我们能够首次确定：1）类固醇如何在体内控制卵巢癌细胞的进展和转移; 2）哪些特定基因是体内转化细胞中雌激素的靶标，3）通过孕酮或雌激素受体拮抗剂阻断这些途径是否阻断转移或肿瘤生长，以及4）雌二醇是如何改变转移部位的为了实现这些目标，我们提出以下具体目标。具体目标1：确定TRP 53和雌二醇在体内影响卵巢肿瘤进展和转移的分子机制。具体目的2：确定突变体TRP 53（R172 H）对体内卵巢癌调节的卵巢肿瘤进展和转移的影响。具体目标3：确定转移性肿瘤生长是否涉及腹膜细胞中的TRP 53状态和类固醇作用。