The majority of human breast cancers express estrogen receptor alpha (ER+ phenotype). Although adjuvant treatment with tamoxifen reduces tumor recurrence and increases survival in approximately 60% of these patients, prolonged use invariably leads to resistance. For the 40% of hormone independent ER+ breast cancers, as well as the ER+ tamoxifen resistant metastases, effective therapeutics are currently lacking. Recently, a novel mechanism of activating estrogen receptor alpha (ER) was elucidated. Cyclin D1 was shown to stimulate the in vivo transcription of reporter genes activated by the ER. This stimulation by cyclin D1 occurred independently of CDK4, the ER was not phosphorylated and, importantly, reporter gene activation occurred in the absence of estrogen. It had previously been well documented that cyclin D1 is overexpressed in approximately 50% of all breast cancers. Therefore, expression of growth response genes mediated by cyclin D1/ER may be involved in the proliferation of hormone independent, ER+ breast cancers and tamoxifen resistant metastases. Compounds which inhibit transcriptional activation of genes by cyclin D1/ER may therefore prevent proliferation of these breast cancer cells. During Phase I research, Saccharomyces cerevisiae yeast strains in which reporter genes are activated by human cyclin D1/ER will be developed. This technology will be utilized in high-throughput screening programs during Phase II. Compounds discovered in such screens may be developed into effective therapeutics for hormone independent breast cancers. PROPOSED COMMERCIAL APPLICATIONS: Breast cancer is the second leading cause of cancer deaths in women in the United States, and the leading cause of cancer deaths in women aged 30 to 70 years. The technology developed during Phase I research will be used in Phase II for discovery of compounds which may be effective therapeutics for the more than 40% of ER+ breast cancers which do not respond to current endocrine therapies.
