Steroid Hormones Regulate Ovarian Cancer Progression and Metastasis

描述(由申请人提供)：了解卵巢类固醇(雌二醇和孕酮)和肿瘤抑制蛋白(TrP53，TP53)的作用和相互作用，对于上皮细胞发生致癌转化形成癌症具有重要的临床意义。卵巢(上皮性)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。临床和流行病学资料显示，卵巢类固醇与卵巢癌之间有很强的联系；约90%的卵巢癌含有TP53突变。不幸的是，人们对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激素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�？和雌激素诱导基因的表达增加介导了卵巢癌肿瘤的生长和转移，这些卵巢癌缺乏功能性TrP53(肿瘤抑制蛋白53或P53)或表达突变的TrP53。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)在体内转化的细胞中，哪些特定基因是雌激素的靶点；3)孕激素或雌激素受体拮抗剂是否可以阻断这些途径，以阻止转移或肿瘤生长；4)雌激素如何改变转移部位。为了实现这些目标，我们提出了以下具体目标。具体目的1：确定TrP53和雌二醇影响卵巢肿瘤进展和转移的分子机制。特定目的2：确定突变型Trp53(R172H)在体内对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与腹膜细胞中TrP53状态和类固醇作用有关。

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.