Steroid Hormones Regulate Ovarian Cancer Progression and Metastasis

描述（由申请人提供）：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，在上皮细胞发生致癌转化形成癌症时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死亡的第五大致命原因，每年死亡人数超过14,000人，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%的卵巢癌存在TP53突变。不幸的是，关于TP53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，这将使我们能够在体内确定雌二醇对卵巢上皮细胞癌的作用。基于对这些小鼠的观察，我们假设ER ？雌激素诱导的基因在缺乏功能性TRP53（肿瘤抑制蛋白53或p53）或表达突变型TRP53的卵巢癌中介导卵巢癌肿瘤的生长和转移。这些强大的小鼠模型与人类卵巢癌细胞系相结合，将使我们首次确定：1)类固醇如何在体内控制卵巢癌细胞的进展和转移；2)在体内转化细胞中，哪些特定基因是雌激素的靶点；3)孕酮或雌激素受体拮抗剂阻断这些途径是否会阻止转移或肿瘤生长；4)雌二醇如何改变转移部位。为实现这些目标，我们提出以下具体目标。特异性目的1：确定TRP53和雌二醇在体内影响卵巢肿瘤进展转移的分子机制。特异性目的2：确定突变体TRP53（R172H）对体内激素调节的卵巢肿瘤进展和转移的影响。特异性目的3：确定转移性肿瘤生长是否涉及腹膜细胞中TRP53状态和类固醇作用。

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.