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：
9538594
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 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9538594
关键词：
Address Age Cancer Cell Growth Cancer cell line Carcinoma Cause of Death Cells Cessation of life Clinical Data Development Diagnostic Disease Disease Management Environment Epithelial Cells Estradiol Estradiol Receptors Estrogen Receptors Estrogens Exhibits Exposure to Gene Targeting Genes Genetic Genomic Instability Goals Growth Hormone replacement therapy Hormones Human Human Cell Line Impairment In Situ Incidence Intercept Life Link Malignant Neoplasms Malignant neoplasm of ovary Mediating Menopausal Symptom Mesentery 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 Peritoneum Progesterone Progesterone Receptors Progestins Recurrence Repressor Proteins Reproducibility Risk Serous Cystadenocarcinoma Site Steroidal Estrogen 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 epidemiologic data estrogenic functional status in vivo insight mouse model mutant mutant mouse model neoplastic cell novel novel therapeutics outcome forecast ovarian neoplasm overexpression public health relevance 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）：当上皮细胞经历致癌转化形成卵巢（上皮）癌时，了解卵巢类固醇（雌二醇和黄体酮）和肿瘤抑制蛋白（TRP53、TP53）的作用和相互作用变得至关重要。至关重要，因为这种疾病是女性第五大致命死因，每年有超过 14,000 人死亡，仍然是一种临床和流行病学数据显示，约 90% 的卵巢癌存在 TP53 突变，但人们对 TP53 状态和类固醇影响卵巢癌的分子机制知之甚少。我们已经建立了独特的小鼠模型，使我们能够在体内定义雌二醇对卵巢上皮细胞癌的作用。在这些小鼠中进行了令人兴奋的观察，我们发现在缺乏功能性 TRP53（肿瘤抑制蛋白 53 或 p53）或表达突变 TRP53 的卵巢癌中，ER 和雌激素诱导基因的表达增加介导卵巢癌肿瘤生长和转移。与人类卵巢癌细胞系相结合将使我们首次确定：1）类固醇如何控制卵巢癌细胞在体内的进展和转移；2）哪些具体的作用；基因是体内转化细胞中雌激素的靶标，3）如果通过孕酮或雌激素受体拮抗剂拦截这些途径，可以阻止转移或肿瘤生长，4）雌二醇如何改变转移位点为了实现这些目标，我们提出以下具体目标。具体目标 1：确定 TRP53 和雌二醇影响卵巢肿瘤体内进展和转移的分子机制。 TRP53(R172H) 对体内激素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 TRP53 状态和腹膜细胞中的类固醇作用。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Endocrine, Paracrine, and Autocrine Signaling Pathways That Regulate Ovulation.

调节排卵的内分泌、旁分泌和自分泌信号通路。

DOI：
发表时间：
2018
期刊：
影响因子：
0
作者：
Richards, JoAnne S;Ascoli, Mario
通讯作者：
Ascoli, Mario

Nutlin-3a: A Potential Therapeutic Opportunity for TP53 Wild-Type Ovarian Carcinomas.

Nutlin-3a：TP53 野生型卵巢癌的潜在治疗机会。

DOI：
发表时间：
2015
期刊：
影响因子：
3.7
作者：
Crane, Erin K;Kwan, Suet;Izaguirre, Daisy I;Tsang, Yvonne T M;Mullany, Lisa K;Zu, Zhifei;Richards, JoAnne S;Gershenson, David M;Wong, Kwong
通讯作者：
Wong, Kwong

Polyploid giant cancer cells and ovarian cancer: new insights into mitotic regulators and polyploidy†.

多倍体巨型癌细胞和卵巢癌：有丝分裂调节因子和多倍体的新见解。

DOI：
发表时间：
2021
期刊：
影响因子：
3.6
作者：
Richards, JoAnne S;Candelaria, Nicholes R;Lanz, Rainer B
通讯作者：
Lanz, Rainer B

The Cell Type-Specific Expression of Lhcgr in Mouse Ovarian Cells: Evidence for a DNA-Demethylation-Dependent Mechanism.

小鼠卵巢细胞中 Lhcgr 的细胞类型特异性表达：DNA 去甲基化依赖性机制的证据。

DOI：
发表时间：
2018-05-01
期刊：
影响因子：
4.8
作者：
Kawai, Tomoko;Richards, JoAnne S;Shimada, Masayuki
通讯作者：
Shimada, Masayuki

Zinc Oxide nanoparticles induce oxidative and proteotoxic stress in ovarian cancer cells and trigger apoptosis Independent of p53-mutation status.

DOI：
10.1016/j.apsusc.2019.05.099
发表时间：
2019-09-01
期刊：
Applied surface science
影响因子：
6.7
作者：
A. Padmanabhan;Mayur Kaushik;R. Niranjan;J. Richards;Br;on Ebright;on;G. Venkatasubbu
通讯作者：
G. Venkatasubbu