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.
The steroid hormones (estrogens and progesterone) impact incidence and risk of ovarian epithelial cell cancer in women. Unfortunately, little is known about how they regulate ovarian tumor growth and metastases. Our unique mouse models will allow us to define for the first time the actions and target genes of estrogens at early stages of ovaria epithelial cell cancer in vivo, providing insights relevant to this cancer in women.