Will Activation of Non-Functional p53 Protein in Breast Cancer Cells Arrest Tumor Progression

PUBLIC ABSTRACT

Most breast cancers possess a mutant protein that is unable to suppress the progression of cancer cells. The protein is termed p53, which in its mutant form accumulates at high concentrations in tumor cells but fails to regulate genes that are necessary to kill the cancerous cells. Converting the mutant inactive protein into its active form might promote the death of cancerous cells and arrest cancer progression. A recently discovered small molecule (PRIMA-1) can restore normal biological function of the mutant p53 protein, although its effect on cancer cells is not yet known. We propose to test the efficacy of PRIMA-1 as an anticancer agent with a focus on hormone-dependent breast cancer cells, i.e., cancer cells that proliferate in response to the hormones present in oral contraceptives or in hormone-replacement therapies (HRT). Our studies will proceed as follows: (1) measure the activity of p53 in tumor cells following PRIMA-1 treatment; (2) determine whether PRIMA-1 can arrest tumor growth in mice implanted with human tumor cells and whether PRIMA-1 can increase the effectiveness of drugs already in use for inhibiting hormone-dependent cancers; and (3) determine whether PRIMA-1 can prevent the initiation or development of tumors in mice administered a known carcinogenic agent that has already been shown to interact via the p53 protein. These studies could potentially lead to the development of a drug that will significantly reduce the incidence of breast cancers in women, especially those who consume synthetic hormones for contraception or HRT.