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Estrogen Receptor AF-1 Interacting Proteins and Peptides
The estrogen receptor (ER) is an important therapeutic target for breast cancer. Several ER-blocking agents, known as selective estrogen receptor modulators (SERMs), have been developed but have limited therapeutic potential because they exert both estrogenic and antiestrogenic properties. Studies strongly suggest that estrogenic SERM activity is mediated by the transcriptional activation domain 1 (AF-1) of the ER. A few AF-1 interacting proteins have already been identified and found to inhibit the ER agonistic activity of SERMs. Thus, we hypothesize that additional AF-1 coregulators exist and aim to discover both novel coregulators and peptides that alter AF-1 function in our project entitled, “Estrogen Receptor AF-1 Interacting Proteins and Peptides.” We anticipate that targeting such coregulators and developing AF-1 specific peptides will allow improved regulation of the ER for therapeutic purposes. The objectives of the proposed project are (1) to identify short peptides and novel proteins that bind to the AF-1 region of the ER, (2) to characterize the identified peptides/proteins for their ability to modulate ER activity, and (3) to identify the specific AF-1 regions involved in peptide/protein recognition. Identification of peptides will be performed by yeast two-hybrid screening of monobody libraries. AF-1 interacting proteins will be identified by several complementary approaches including glutathione-s-transferase pull-down assays using mammalian breast and endometrial cancer cell extracts, yeast two-hybrid screening of breast-specific cDNA libraries, and finally T7 phage display of breast-specific cDNA libraries. Candidate peptides/proteins that exhibit ER antagonist activity by estrogen-responsive reporter assays will be further tested for therapeutic potential using thymidine incorporation assays. Finally, the AF-1 amino acid residues involved in recognition of peptides/proteins showing therapeutic potential will be determined by mapping studies. The proposed studies will lead to the discovery of novel proteins targeted in the ER signaling pathway and contribute to our understanding of the mechanisms by which the ER promotes the initiation and development of breast cancer. Results from these studies will also allow the development of peptide inhibitors and small molecule mimetics that block ER function and ultimately aid in the discovery of novel therapeutic agents for breast cancer prevention and treatment.
Breast cancer is a leading cause of cancer among women in the U.S. Thus, the development of drugs for both the prevention and treatment of breast cancer is of high priority. Currently available drugs, such as tamoxifen and raloxifene, are known as selective estrogen receptor modulators (SERMs). SERMs inhibit breast cancer growth by partially blocking the function of estrogen receptors found in breast cancer cells. Estrogen receptors are proteins that bind to estrogen and promote the development or progression of breast cancer by increasing cell growth. Although SERMs have been useful for treating and reducing the incidence of hormone-dependent breast cancer, they do not consistently reduce cancer growth and may even cause undesirable side effects such as an increased risk for uterine cancer. Evidence suggests that SERMs may fail to reduce cancer growth because they do not block the function of a particular region of the estrogen receptor, known as the transcriptional activation domain 1 (AF-1). Studies have also shown that certain proteins that interact with the AF-1 may block the undesirable effects of SERMs. Thus, our goal is to discover new AF-1 interacting proteins that may regulate AF-1 function and to develop drugs that specifically inhibit AF-1 activity in our project entitled, “Estrogen Receptor AF-1 Interacting Proteins and Peptides.” Our studies will allow us to better understand how the estrogen receptor promotes breast cancer growth and will also allow us to develop inhibitors that block AF-1 function, ultimately aiding in the development of improved breast cancer therapy.