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p53-activating Compounds as Therapeutic Tools for Progestin-accelerated Mammary Tumors
Background : Exposure to synthetic progestin increases the risk of breast cancer in post-menopausal women on hormone replacement therapy. This likely occurs through stimulation of a sub-clinical population of cancer cells due to altered levels of functional p53 protein that plays a critical role in cancer surveillance. DMBA-induced mammary tumors in rats develop faster in p53-deficient animals; however, tumor growth is reduced by deficiency in the progesterone receptor. In humans, over 50% tumors are deficient in one or both alleles of p53. These observations have generated interest in therapeutic approaches that involve restoring functional p53 in tumor cells. This study will test the ideas that exogenous progestin stimulates DMBA-induced mammary tumors in rats via the PR, and that compounds that re-activate the endogenous p53 can inhibit growth of hormone-stimulated breast tumors. Hypothesis: Progestins stimulate DMBA-induced mammary tumors by suppressing p53-dependent apoptosis and stimulating angiogenesis Specific Aims: 1a) Determine if commonly consumed synthetic progestins, MPA and norgestrel, promote DMBA-induced mammary carcinogenesis in rats, and 1b) if the mechanism involves angiogenesis. 2) Determine if PRIMA-1 (p53 reactivation induction of massive apoptosis) and resveratrol inhibit growth of progestin-stimulated tumors, and 3) Determine if PRIMA-1 and resveratrol alter expression of genes associated with p53-dependent apoptosis and/or angiogenesis. Study Design : The effect of MPA and norgestrel on DMBA-induced mammary carcinogenesis will be examined in Sprague-Dawley rats. The importance of progestin dose and time of treatment will be tested and expression of pro-angiogenic genes will be analyzed. Similarly, influence of PRIMA-1 and resveratrol on delaying or preventing progestin accelerated tumors will be assessed and changes in gene expression will be monitored with particular attention to genes involved in angiogenesis and p53-dependent apoptosis. Potential Outcome and Benefits : The proposed study will analyze the effect of synthetic progestins and p53-activating compounds on signaling pathways that may play a role in mammary carcinogenesis. If successful, this study will identify targets that regulate growth of progestin-accelerated tumors. Moreover, these targets may be relevant for reducing breast cancer risk in women exposed to hormone replacement or other hormone-based therapies including contraception or fertility enhancement.
Breast cancer afflicts millions of women in the U.S. and is a major world-wide health problem. Recent studies show that post-menopausal women treated with estrogen and the synthetic progestin medroxyprogesterone acetate (MPA) as hormone replacement therapy are at increased risk of developing breast cancer. One possible explanation for this increased risk is that MPA promotes growth of a sub clinical and/or quiescent population of breast cancer cells. We have confirmed this hypothesis experimentally in a rat model for chemically-induced breast cancer. It is known that p53, a tumor suppressor protein, plays an important role in cancer surveillance and helps to destroy cells that could potentially lead to tumor formation. However, in many tumor cells p53 function is partially or completely lost, thus allowing tumors to accumulate mutations and become malignant at an increased rate. One approach to inhibiting proliferation of p53-deficient breast cancers is to re-activate normal functions of p53. Two small molecule compounds, PRIMA-1 and resveratrol, were recently discovered that can activate mutant and wild-type p53 in cancer cells. These compounds are believed to have significant therapeutic potential, but additional studies are needed to determine how these compounds affect the growth of hormone-dependent breast cancer cells. This proposal has three specific goals. The first goal is to determine whether two commonly used progestins, MPA and norgestrel, promote growth of chemically-induced tumors in rats and if the mechanism of promoting growth involves formation of new blood vessels; the second goal of the proposal is to determine if p53-activating compounds PRIMA-1 and resveratrol inhibit growth of tumors in the presence of exogenous progestin. The third goal of the proposal is to analyze the mechanism by which changes in gene expression associated with PRIMA-1- or resveratrol suppress tumor growth. The therapeutic approach explored in this proposal involves activating the intrinsic potential of p53 as a cancer surveillance protein. This approach could provide a powerful tool to prevent or inhibit tumor growth and is likely to lead to deeper insight into the mechanisms and pathology of breast cancer. Importantly, the potential of this approach in women being treated with hormone replacement therapy or other hormone-based therapies will be thoroughly explored in this study.