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STAT5 as a Common Mediator of Estrogen and Growth Factor Signaling in Breast Cancer
Growth of human breast tumors is often initially estrogen (17b-estradiol, or E2) dependent, allowing adjuvant anti-estrogen therapy in 40-70% of tumors. Tumor progression is associated with the overexpression of growth factor receptors, such as members of the human epidermal growth factor receptor (HER) family. Overexpression of HER1, or the EGF receptor (EGFR), frequently is found in estrogen receptor negative (ER-) breast cancers, which is characteristic of later stage, and more aggressive tumors. Our studies have provided compelling evidence that the STAT5 transcription factor is one of the downstream signaling molecules that is activated in EGFR overexpressing cells. The STAT5 proteins (STAT5a and STAT5b) are activated by tyrosine phosphorylation, resulting in dimerization, translocation to the nucleus, and binding to STAT5 regulatory elements in the promoters of genes. There is increasing evidence that the pathways that regulate E2-induced growth of breast cancer cells and those that regulate EGF-induced growth of these cells require common downstream mediators. Our work has provided evidence that signaling through the ER regulates STAT5 activation in a cell context dependent manner. Our hypothesis is that STAT5 serves as a common downstream effector of both E2- and EGF-induced signaling and thus may provide a common target point for modulating the transition between E2-dependent and EGF-dependent growth of breast cancer cells. We will address the following Specific Aims: I. Characterize the interaction between the STAT5 and ER signaling pathways in breast cancer models; and II. Determine the role of STAT5 signaling in the promotion of E2-induced transcriptional activation, proliferation and tumorigenesis. In order to address these aims we will human breast cancer cell line model systems that are either ER(-) or ER(+). STAT5 activation will be analyzed by 1) tyrosine phosphorylation of specific sites; 2) DNA-binding to STAT5 regulatory elements; and 3) transcriptional assays. Single cell assays of BrdU (bromodeoxyuridine) incorporation will be used to measure DNA-synthesis. Primary human breast tumor tissue will be analyzed for the presence of ER and STAT5 tyrosine phosphorylation. If STAT5 is a common downstream mediator of both estrogen-dependent and independent growth of breast cancer, it will provide a means of targeted therapy effective in both E2-sensitive and E2-resistant tumors.
Tumorigenesis, or the process of tumor formation, results from normal cellular processes gone awry. These processes result from a communication between proteins at the surface of the cell (receptors) that sense the environment outside the cell (extracellular milieu) and then relay the message to the inside (cytoplasm) of the cell and eventually to the nucleus where genes are regulated; resulting in an increase in DNA-synthesis, cellular proliferation, malignant transformation and tumor formation. Growth of human breast tumors is often initially estrogen (17b-estradiol or E2) dependent, and in 40-70% of cases, responsive to adjuvant anti-estrogen therapy. Unfortunately, breast cancer progression frequently is associated with loss of estrogen responsiveness, thus rendering these treatments ineffective. Breast tumor cells that no longer express the estrogen receptor (ER-) frequently overexpress receptors of the human epidermal growth factor receptor (HER) family. HER2/neu is the target of the drug, Herceptin; while HER1 or epidermal growth factor EGF receptor (EGFR) is frequently overexpressed (upregulated) in later stage, aggressive breast cancers. The process by which the tumor cell undergoes the transition from estrogen responsive to estrogen resistant and growth factor receptor dependent is not well understood. However, these tumors clearly lose their dependence on estrogen for growth and become dependent on growth factors instead. There is increasing evidence that the estrogen-mediated and growth factor-mediated pathways of tumor proliferation may require common downstream mediators. We have evidence that one common pathway is the signal transducer and activator of transcription (STAT) pathway. Our work has identified a specific protein (STAT5) that is activated in breast tumor cells. Upon activation, STAT5 translocates from the cytoplasm of the cell to the nucleus where it binds directly to DNA and regulates genes involved in cellular proliferation. In this application we propose to (1) characterize the interaction between STAT5 and ER signaling pathways in breast cancer models; and (2) to determine the role of STAT5 signaling in the promotion of E2-induced transcriptional activation, proliferation, and tumorigenesis. Our goal is that understanding the role of STAT5 activation in the transition of breast tumors from E2-dependent to E2-independent will lead to the development of STAT5 targeted therapies.